Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof

ABSTRACT

The present invention relates to, inter alia, pharmaceutical compositions comprising a polyunsaturated fatty acid and to methods of using the same to treat or prevent cardiovascular-related diseases.

PRIORITY CLAIM

This application claims priority to U.S. provisional patent applicationSer. No. 61/766,464, filed Feb. 19, 2013, the entire contents of whichis incorporated herein by reference and relied upon.

BACKGROUND

Cardiovascular disease is one of the leading causes of death in theUnited States and most European countries. It is estimated that over 70million people in the United States alone suffer from a cardiovasculardisease or disorder including but not limited to high blood pressure,coronary heart disease, dyslipidemia, congestive heart failure andstroke. A need exists for improved treatments for cardiovasculardiseases and disorders.

SUMMARY

In one embodiment, the invention provides a pharmaceutical compositioncomprising EPA (e.g., ethyl eicosapentaenoate) or a pharmaceuticallyacceptable salt or ester thereof, and a hydroxyl compound or apharmaceutically acceptable salt or derivative thereof.

In any embodiment disclosed herein, the pharmaceutical composition maycomprise at least about 80%, by weight of all fatty acids (and/orderivatives thereof) present, ethyl eicosapentaenoate (e.g., at leastabout 90%, at least about 95%, or at least about 96%, by weight of allfatty acids or derivatives thereof present, ethyl eicosapentaenoate). Inany embodiment disclosed herein, the pharmaceutical composition mayinclude substantially no DHA or esters thereof, essentially no DHA oresters thereof, or no more than about 5%, by weight of all fatty acids(and/or derivatives thereof) present, DHA or esters thereof.

In other embodiments, the present invention provides methods of treatingand/or preventing a cardiovascular-related disease comprisingco-administering a pharmaceutical composition or composition(s)comprising EPA and a hydroxyl compound.

In any of the foregoing embodiments, the EPA and the hydroxyl compoundcan be co-formulated as a single dosage unit or can be formulated as twoto a plurality of dosage units for coordinated, combination orconcomitant administration

In other embodiments, the present invention provides methods of treatingor preventing a cardiovascular-related disease using compositions asdescribed herein. In some embodiments, the cardiovascular-relateddisease is hypertriglyceridemia.

These and other embodiments of the present invention will be disclosedin further detail herein below.

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any manner. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

The use of numerical values in the various quantitative values specifiedin this application, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about.” In this manner,slight variations from a stated value can be used to achievesubstantially the same results as the stated value. Also, the disclosureof ranges is intended as a continuous range including every valuebetween the minimum and maximum values recited as well as any rangesthat can be formed by such values. Also disclosed herein are any and allratios (and ranges of any such ratios) that can be formed by dividing arecited numeric value into any other recited numeric value. Accordingly,the skilled person will appreciate that many such ratios, ranges, andranges of ratios can be unambiguously derived from the numerical valuespresented herein and in all instances such ratios, ranges, and ranges ofratios represent various embodiments of the present invention.

In one embodiment, compositions of the invention comprise apolyunsaturated fatty acid as an active ingredient. In anotherembodiment, compositions of the invention comprise EPA as an activeingredient. The term “EPA” as used herein refers to eicosapentaenoicacid (e.g. eicosa-5,8,11,14,17-pentaenoic acid) and/or apharmaceutically acceptable ester, derivative, conjugate or saltthereof, or mixtures of any of the foregoing.

In one embodiment, the EPA comprises all-ciseicosa-5,8,11,14,17-pentaenoic acid. In another embodiment, the EPA isin the form of an eicosapentaenoic acid ester. In another embodiment,the EPA comprises a C₁-C₅ alkyl ester of EPA. In another embodiment, theEPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acidmethyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoicacid butyl ester. In still another embodiment, the EPA comprises all-ciseicosa-5,8,11,14,17-pentaenoic acid ethyl ester.

In still other embodiments, the EPA comprises ethyl-EPA, lithium EPA,mono, di- or triglyceride EPA or any other ester or salt of EPA, or thefree acid form of EPA. The EPA may also be in the form of a2-substituted derivative or other derivative which slows down its rateof oxidation but does not otherwise change its biological action to anysubstantial degree.

The term “pharmaceutically acceptable” in the present context means thatthe substance in question does not produce unacceptable toxicity to thesubject or interaction with other components of the composition.

In one embodiment, EPA present in a composition of the inventioncomprises ultra-pure EPA. The term “ultra-pure” as used herein withrespect to EPA refers to a composition comprising at least 96% by weightEPA (as the term “EPA” is defined and exemplified herein). Ultra-pureEPA can comprise even higher purity EPA, for example at least 97% byweight EPA or at least 98% by weight EPA, wherein the EPA is any form ofEPA as set forth herein. Ultra-pure EPA can further be defined (e.g.impurity profile) by any of the description of EPA provided herein.

In other embodiments, EPA is present in a composition of the inventionin an amount of about 50 mg to about 5000 mg, about 75 mg to about 2500mg, or about 100 mg to about 1000 mg, for example about 50 mg, about 75mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg,about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg,about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg,about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg,about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg,about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg, about 2700mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg,about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg, about 3050mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg,about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg,about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg,about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about 4100mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about4225 mg, about 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg,about 4350 mg, about 4375 mg, about 4400 mg, about 4425 mg, about 4450mg, about 4475 mg, about 4500 mg, about 4525 mg, about 4550 mg, about4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about 4675 mg,about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg, about 4800mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about4925 mg, about 4950 mg, about 4975 mg, or about 5000 mg.

In one embodiment, compositions of the invention comprise a hydroxylcompound as an active ingredient. The term “hydroxyl compound” as usedherein refers to compounds of formulas I, II, III, IV, V, VI, VII, VIII,IX, and pharmaceutically acceptable salts, hydrates, enantiomers,diastereomers, racemates or mixtures of stereoisomers thereof.

As used herein with respect to the hydroxyl compound, the term “alkylgroup” means a saturated, monovalent unbranched or branched hydrocarbonchain. Examples of alkyl groups include, but are not limited to,(C₁-C₆)alkyl groups, such as methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2 methyl 2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2 methyl-3-butyl, 2,2 dimethyl 1-propyl,2-methyl-1-pentyl, 3 methyl-1-pentyl, 4 methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl 2 pentyl, 2,2 dimethyl 1butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl,pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, suchas heptyl, and octyl. An alkyl group can be unsubstituted or substitutedwith one or two suitable substituents.

As used herein with respect to the hydroxyl compound, the term an“alkenyl group” means a monovalent unbranched or branched hydrocarbonchain having one or more double bonds therein. The double bond of analkenyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkenyl groups include, but are not limited to(C₂-C₆)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl,butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted orsubstituted with one or two suitable substituents.

As used herein with respect to the hydroxyl compound, the term an“alkynyl group” means monovalent unbranched or branched hydrocarbonchain having one or more triple bonds therein. The triple bond of analkynyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkynyl groups include, but are not limited to,(C₂-C₆)alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substitutedwith one or two suitable substituents.

As used herein with respect to the hydroxyl compound, the term an “arylgroup” means a monocyclic or polycyclic-aromatic radical comprisingcarbon and hydrogen atoms. Examples of suitable aryl groups include, butare not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl,azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties suchas 5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, the arylgroup is a monocyclic ring, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)aryl”.

As used herein with respect to the hydroxyl compound, the term an“heteroaryl group” means a monocyclic- or polycyclic aromatic ringcomprising carbon atoms, hydrogen atoms, and one or more heteroatoms,preferably 1 to 3 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. Illustrative examples of heteroaryl groups include,but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazyl,triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and(1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl,thiophenyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, andoxazolyl. A heteroaryl group can be unsubstituted or substituted withone or two suitable substituents. Preferably, a heteroaryl group is amonocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to3 heteroatoms, referred to herein as “(C₂-C₅)heteroaryl”.

As used herein with respect to the hydroxyl compound, the term“cycloalkyl group” means a monocyclic or polycyclic saturated ringcomprising carbon and hydrogen atoms and having no carbon-carbonmultiple bonds. Examples of cycloalkyl groups include, but are notlimited to, (C₃-C₇)cycloalkyl groups, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic andbicyclic terpenes. A cycloalkyl group can be unsubstituted orsubstituted by one or two suitable substituents. Preferably, thecycloalkyl group is a monocyclic ring or bicyclic ring.

As used herein with respect to the hydroxyl compound, the term“heterocycloalkyl group” means a monocyclic or polycyclic ringcomprising carbon and hydrogen atoms and at least one heteroatom,preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, andsulfur, and having no unsaturation. Examples of heterocycloalkyl groupsinclude pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl,piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,and pyranyl. A heterocycloalkyl group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, theheterocycloalkyl group is a monocyclic or bicyclic ring, morepreferably, a monocyclic ring, wherein the ring comprises from 3 to 6carbon atoms and form 1 to 3 heteroatoms, referred to herein as(C₁-C₆)heterocycloalkyl.

As used herein, the terms “heterocyclic radical” or “heterocyclic ring”mean a heterocycloalkyl group or a heteroaryl with respect to thehydroxyl compound group.

As used herein with respect to the hydroxyl compound, the term “alkoxygroup” means an —O-alkyl group, wherein alkyl is as defined above. Analkoxy group can be unsubstituted or substituted with one or twosuitable substituents. Preferably, the alkyl chain of an alkyloxy groupis from 1 to 6 carbon atoms in length, referred to herein as“(C₁-C₆)alkoxy”.

As used herein with respect to the hydroxyl compound, the term “aryloxygroup” means an —O-aryl group, wherein aryl is as defined above. Anaryloxy group can be unsubstituted or substituted with one or twosuitable substituents. Preferably, the aryl ring of an aryloxy group isa monocyclic ring, wherein the ring comprises 6 carbon atoms, referredto herein as “(C₆)aryloxy”.

As used herein with respect to the hydroxyl compound, the term “benzyl”means —CH₂-phenyl.

As used herein with respect to the hydroxyl compound, the term “phenyl”means —C₆H₅. A phenyl group can be unsubstituted or substituted with oneor two suitable substituents, wherein the subtituent replaces an H ofthe phenyl group. As used herein, “Ph,” represents a phenyl group or asubstituted phenyl group.

As used herein with respect to the hydroxyl compound, the term“hydrocarbyl” group means a monovalent group selected from (C₁-C₈)alkyl,(C₂-C₈)alkenyl, and (C₂-C₈)alkynyl, optionally substituted with one ortwo suitable substituents. Preferably, the hydrocarbon chain of ahydrocarbyl group is from 1 to 6 carbon atoms in length, referred toherein as “(C₁-C₆)hydrocarbyl”.

As used herein with respect to the hydroxyl compound, a “carbonyl” groupis a divalent group of the formula C(O).

As used herein with respect to the hydroxyl compound, the term“alkoxycarbonyl” group means a monovalent group of the formula—C(O)-alkoxy. Preferably, the hydrocarbon chain of an alkoxycarbonylgroup is from 1 to 8 carbon atoms in length, referred to herein as a“lower alkoxycarbonyl” group.

As used herein with respect to the hydroxyl compound, a “carbamoyl”group means the radical —C(O)N(R′)₂, wherein R′ is chosen from the groupconsisting of hydrogen, alkyl, and aryl.

As used herein with respect to the hydroxyl compound, “halogen” meansfluorine, chlorine, bromine, or iodine. Accordingly, the meaning of theterms “halo” and “Hal” encompass fluoro, chloro, bromo, and iodo.

As used herein with respect to the hydroxyl compound, a “suitablesubstituent” means a group that does not nullify the synthetic orpharmaceutical utility of the compounds of the invention or theintermediates useful for preparing them. Examples of suitablesubstituents include, but are not limited to: (C₁-C₈)alkyl;(C₁-C₈)alkenyl; (C₁-C₈)alkynyl; (C₆)aryl; (C₂-C₅)heteroaryl;(C₃-C₇)cycloalkyl; (C₁-C₈)alkoxy; (C₆)aryloxy; —CN; —OH; oxo; halo,—CO₂H; —NH₂; —NH((C₁-C₈)alkyl); —N((C₁-C₈)alkyl)₂; —NH((C₆)aryl);—N((C₆)aryl)₂; —CHO; —CO((C₁-C₈)alkyl); —CO((C₆)aryl);—CO₂((C₁-C₈)alkyl); and —CO₂((C₆)aryl). One of skill in the art canreadily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compound of the invention.

In some embodiments, the hydroxyl compound is a compound of Formula I:

or a pharmaceutically acceptable salt, hydrate, solvate or mixturethereof, wherein:

-   -   (a) each occurrence of m is independently an integer ranging        from 0 to 5;    -   (b) each occurrence of n is independently an integer ranging        from 3 to 7;    -   (c) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4        and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;    -   (d) each occurrence of R¹, R², R¹¹, and R¹² is independently H,        (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, or benzyl,        wherein R¹, R², R¹¹, and R¹² are not each simultaneously H; and    -   (e) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,        OH, COOH, COOR⁵, SO₃H,

wherein:

-   -   (i) Y¹ and Y² are not each simultaneously (C₁-C₆)alkyl;    -   (ii) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (iii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups; and    -   (iv) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.

In some embodiments, the hydroxyl compound is a compound of Formula II:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein:

-   -   (a) each occurrence of m is independently an integer ranging        from 3 to 7;    -   (b) each occurrence of n is independently an integer ranging        from 0 to 5;    -   (c) X is (CH₂), or Ph, wherein z is an integer from 0 to 4 and        Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;    -   (d) each occurrence of Y¹ and Y² independently (C₁-C₆)alkyl, OH,        COOH, COOR⁷, SO₃H,

wherein:

-   -   (i) R⁷ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁸ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups,    -   (iii) each occurrence of R⁹ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl;    -   (e) R³ and R⁴ are (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        phenyl, or benzyl;    -   (f) R⁵ and R⁶ are H, halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,        (C₆)aryloxy, CN, or NO₂, N(R⁵)₂ where R⁵ is H, (C₁-C₄)alkyl,        phenyl, or benzyl;    -   (g) C*¹ and C*² represent independent chiral-carbon centers        wherein each center may independently be R or S.

In some embodiments, the hydroxyl compound is a compound of Formula III:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   -   (a) each occurrence of R¹, R², R⁶, R⁷, R¹¹, or R¹² is        independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,        (C₂-C₆)alkynyl, phenyl, or benzyl;    -   (b) each occurrence of n is independently an integer ranging        from 1 to 7;    -   (c) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4        and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;    -   (d) each occurrence of m is independently an integer ranging        from 0 to 4;    -   (e) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,        CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups;    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and    -   (f) b is 0 or 1 and optionally the ring contains the presence of        one or more additional carbon-carbon bonds that when present        complete one or more carbon-carbon double bonds such that when b        is 0 the maximum number of carbon-carbon bonds is two or when b        is 1 the maximum number of carbon-carbon bonds is three.

In some embodiments, the hydroxyl compound is a compound of Formula IV:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   -   (a) each occurrence of R¹, R², R⁶, R⁷, R¹¹, or R¹² is        independently H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        phenyl, or benzyl;    -   (b) each occurrence of n is independently an integer ranging        from 1 to 7;    -   (c) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4        and Ph is a 1,2-, 1,3-, or 1,4-substituted phenyl group;    -   (d) each occurrence of m is independently an integer ranging        from 0 to 4;    -   (e) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,        CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups;    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and    -   (f) each occurrence of b is independently 0 or 1 and optionally        each of the rings independently contains the presence of one or        more additional carbon-carbon bonds that when present complete        one or more carbon-carbon double bonds such that when b is 0 the        maximum number of carbon-carbon bonds is two or when b is 1 the        maximum number of carbon-carbon bonds is three.

In some embodiments, the hydroxyl compound is a compound of Formula V:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   -   (a) each occurrence of R¹, R², R⁶, R⁷, R¹¹, or R¹² is        independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,        (C₂-C₆)alkynyl, phenyl, or benzyl;    -   (b) each occurrence of n is independently an integer ranging        from 1 to 7;    -   (c) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4        and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;    -   (d) each occurrence of m is independently an integer ranging        from 0 to 4;    -   (e) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,        CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups;    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and    -   (f) b is 0 or 1 and optionally the ring contains one or more        carbon-carbon bonds that when present complete one or more        carbon-carbon double bonds.

In some embodiments, the hydroxyl compound is a compound of Formula VI:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein:

-   -   (a) each occurrence of R¹, R², R⁶, R⁷, R¹¹, or R¹² is        independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,        (C₂-C₆)alkynyl, phenyl, or benzyl;    -   (b) each occurrence of n is independently an integer ranging        from 1 to 7;    -   (c) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4        and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;    -   (d) each occurrence of m is independently an integer ranging        from 0 to 4;    -   (e) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,        CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups; and    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and    -   (f) b is 0 or 1 and optionally the ring contains one or more        carbon-carbon bonds that when present complete one or more        carbon-carbon double bonds.

In some embodiments, the hydroxyl compound is a compound of Formula VII:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   -   (a) Z is CH₂, CH═CH, or phenyl, where each occurrence of m is        independently an integer ranging from 1 to 9, but when Z is        phenyl then its associated m is 1;    -   (b) G is (CH₂)_(x), where x is 1, 2, 3, or 4, CH₂CH═CHCH₂,        CH═CH, CH₂-phenyl-CH₂, or phenyl;    -   (c) each occurrence of Y¹ and Y² is independently L, V,        C(R¹)(R²)—(CH₂)c-C(R³)(R⁴)—(CH₂)n-Y, or C(R¹)(R²)—(CH₂)c-V where        c is 1 or 2 and n is an integer ranging from 0 to 4; when G is        (CH₂)_(x), where x is 1, 2, 3, or 4, W² is CH₃;    -   (d) each occurrence of R¹ or R² is independently (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, or benzyl or when one or        both of Y¹ and Y² is C(R¹)(R²)—(CH₂)c-C(R³)(R⁴)—(CH₂)n-W, then        R¹ and R² can both be H to form a methylene group;    -   (e) R³ is H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkoxy, phenyl, benzyl, Cl, Br, CN, NO₂, or CF₃;    -   (f) R⁴ is OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkoxy, phenyl, benzyl, Cl, Br, CN, NO₂, or CF₃;    -   (g) L is C(R¹)(R²)—(CH₂)n-W;    -   (h) V is:

-   -   (i) each occurrence of W is independently OH, COOH, CHO, COOR⁵,        SO₃H,

wherein:

-   -   (i) R⁵ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁶ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, (C₁-C₆) alkoxy, or phenyl        groups;    -   (iii) each occurrence of R⁷ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and    -   (j) X is (CH₂)_(z) or PH, wherein z is an integer from 0 to 4.

In some embodiments, the hydroxyl compound is a compound of FormulaVIII:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   -   (a) Z is CH₂, CH═CH, or phenyl, where each occurrence of m is        independently an integer ranging from 1 to 9, but when Z is        phenyl then its associated m is 1;    -   (b) G is (CH₂)_(x), where x is 1, 2, 3, or 4, CH₂CH═CHCH₂,        CH═CH, CH₂-phenyl-CH₂, or phenyl;    -   (c) each occurrence of Y¹ and Y² is independently L, V,        C(R¹)(R²)(CH₂)c-C(R³)(R⁴)—(CH₂)_(n)-Y, or C(R¹)(R²)—(CH₂)c-V        where c is 1 or 2 and n is an integer ranging from 0 to 4; when        G is (CH₂)_(x), where x is 1, 2, 3, or 4, W² is CH₃;    -   (d) each occurrence of R¹ or R² is independently (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, or benzyl or when one or        both of Y¹ and Y² is C(R¹)(R²)—(CH₂)c-C(R³)(R⁴)—(CH₂)n-W, then        R¹ and R² can both be H to form a methylene group;    -   (e) R³ is H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkoxy, phenyl, benzyl, Cl, Br, CN, NO₂, or CF₃;    -   (f) R⁴ is OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkoxy, phenyl, benzyl, Cl, Br, CN, NO₂, or CF₃;    -   (g) L is C(R¹)(R²)—(CH₂)n-W;    -   (h) V is:

-   -   (i) each occurrence of W is independently OH, COOH, CHO, COOR⁵,        SO₃H,

wherein:

-   -   (i) R⁵ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁶ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, (C₁-C₆) alkoxy, or phenyl        groups; and    -   (iii) each occurrence of R⁷ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.

In some embodiments, the hydroxyl compound is a compound of Formula IX:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   -   (a) Z is CH₂, CH═CH, or phenyl, where each occurrence of m is        independently an integer ranging from 1 to 9, but when Z is        phenyl then its associated m is 1;    -   (b) G is (CH₂)_(x), where x is 1, 2, 3, or 4, CH₂CH═CHCH₂,        CH═CH, CH₂-phenyl-CH₂, or phenyl;    -   (c) each occurrence of Y¹ and Y² is independently L, V,        C(R¹)(R²)—(CH₂)c-C(R³)(R⁴)—

(CH₂)_(n)—Y, or C(R¹)(R²)—(CH₂)c-V where c is 1 or 2 and n is an integerranging from 0 to 4; when G is (CH₂)_(x), where x is 1, 2, 3, or 4, W²is CH₃;

-   -   (d) each occurrence of R¹ or R² is independently (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, or benzyl or when one or        both of Y¹ and Y² is C(R¹)(R²)—(CH₂)c-C(R³)(R⁴)—(CH₂)n-W, then        R¹ and R² can both be H to form a methylene group;    -   (e) R³ is H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkoxy, phenyl, benzyl, Cl, Br, CN, NO₂, or CF₃;    -   (f) R⁴ is OH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkoxy, phenyl, benzyl, Cl, Br, CN, NO₂, or CF₃;    -   (g) L is C(R¹)(R²)—(CH₂)n-W;    -   (h) V is:

-   -   (i) each occurrence of W is independently OH, COOH, CHO, COOR⁵,        SO₃H,

wherein:

-   -   (i) R⁵ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁶ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, (C₁-C₆) alkoxy, or phenyl        groups; and    -   (iii) each occurrence of R⁷ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.

In some embodiments, the hydroxyl compound is8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.

In some embodiments, the hydroxyl compound is present in a compositionof the invention in a an amount less than, approximately equal to, orgreater than an amount effective for treating a disease or disorder ifthe hydroxyl compound is administered as a monotherapy. In someembodiments, the composition comprises about 2 mg to about 1000 mg ofhydroxyl compound, about 5 mg to about 500 mg of hydroxyl compound,about 7 mg to about 200 mg of hydroxyl compound, about 10 mg to about100 mg of hydroxyl compound, or about 7 mg to about 10 mg of hydroxylcompound, for example about 2 mg, about 3 mg, about 4 mg, about 5 mg,about 6 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 8 mg, about 9mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg,about 15 mg, about 20 mg, about 25 mg, about 28 mg, about 30 mg, about35 mg, about 40 mg, about 42 mg, about 45 mg, about 49 mg, about 50 mg,about 55 mg, about 56 mg, about 60 mg, about 63 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg,about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg,about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg,about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg,about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg,about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg,about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg,about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg,about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg,about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg,about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg,about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg,about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg,about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg,about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg,about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg,about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg,about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg,about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg,about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg,about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg,about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg,about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg,about 700 mg, about 705 mg, about 710 mg, about 715 mg, about 720 mg,about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg,about 750 mg, about 755 mg, about 760 mg, about 765 mg, about 770 mg,about 775 mg, about 780 mg, about 785 mg, about 790 mg, about 795 mg,about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg,about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg,about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg,about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg,about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg,about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg,about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg,about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, orabout 1000 mg.

In various embodiments, one or more antioxidants can be present in acomposition according to the present invention. Non-limiting examples ofsuitable antioxidants include tocopherol, lecithin, citric acid and/orascorbic acid. One or more antioxidants, if desired, are typicallypresent in the composition in an amount of about 0.01% to about 0.1%, byweight, or about 0.025% to about 0.05%, by weight.

In one embodiment, a composition of the invention contains not more thanabout 10%, not more than about 9%, not more than about 8%, not more thanabout 7%, not more than about 6%, not more than about 5%, not more thanabout 4%, not more than about 3%, not more than about 2%, not more thanabout 1%, or not more than about 0.5%, by weight of total fatty acids,docosahexaenoic acid or derivative thereof such as E-DHA, if any. Inanother embodiment, a composition of the invention containssubstantially no docosahexaenoic acid or derivative thereof such asE-DHA. In still another embodiment, a composition of the inventioncontains no docosahexaenoic acid or E-DHA.

In another embodiment, EPA represents at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 95%, atleast about 97%, at least about 98%, at least about 99%, or 100%, byweight, of all fatty acids present in a composition of the invention.

In another embodiment, a composition of the invention contains less than30%, less than 20%, less than 10%, less than 9%, less than 8%, less than7%, less than 6%, less than 5%, less than 4%, less than 3%, less than2%, less than 1%, less than 0.5% or less than 0.25%, by weight of thetotal composition or by weight of the total fatty acid content, of anyfatty acid other than EPA, or derivative thereof. Illustrative examplesof a “fatty acid other than EPA” include linolenic acid (LA) orderivative thereof such as ethyl-linolenic acid, arachidonic acid (AA)or derivative thereof such as ethyl-AA, docosahexaenoic acid (DHA) orderivative thereof such as ethyl-DHA, alpha-linolenic acid (ALA) orderivative thereof such as ethyl-ALA, stearadonic acid (STA) orderivative thereof such as ethyl-SA, eicosatrienoic acid (ETA) orderivative thereof such as ethyl-ETA and/or docosapentaenoic acid (DPA)or derivative thereof such as ethyl-DPA.

In another embodiment, a composition of the invention has one or more ofthe following features: (a) eicosapentaenoic acid ethyl ester representsat least 96%, at least 97%, or at least 98%, by weight, of all fattyacids present in the composition; (b) the composition contains not morethan 4%, not more than 3%, or not more than 2%, by weight, of totalfatty acids other than eicosapentaenoic acid ethyl ester; (c) thecomposition contains not more than 0.6%, 0.5%, or 0.4% of any individualfatty acid other than eicosapentaenoic acid ethyl ester; (d) thecomposition has a refractive index (20° C.) of about 1 to about 2, about1.2 to about 1.8 or about 1.4 to about 1.5; (e) the composition has aspecific gravity (20° C.) of about 0.8 to about 1.0, about 0.85 to about0.95 or about 0.9 to about 0.92; (f) the composition contains not morethan 20 ppm, 15 ppm or 10 ppm heavy metals, (g) the composition containsnot more than 5 ppm, 4 ppm, 3 ppm, or 2 ppm arsenic, and/or (h) thecomposition has a peroxide value not more than 5, 4, 3, or 2 meq/kg.

In another embodiment, a composition useful in accordance with theinvention comprises a hydroxyl compound and a fatty acid componentcomprising, consisting essentially of or consisting of at least 95% byweight ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5% byweight ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% byweight ethyl nonadecapentaenoate (NDPA-E), about 0.2% to about 0.45% byweight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by weightethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethylheneicosapentaenoate (HPA-E). In another embodiment, the composition ispresent in a capsule shell. In still another embodiment, the capsuleshell contains no chemically modified gelatin.

In another embodiment, a composition useful in accordance with theinvention comprises a hydroxyl compound and a fatty acid componentcomprising, consisting essentially of or consisting of at least 80%,90%, 95%, 96% or 97%, by weight, ethyl eicosapentaenoate, about 0.2% toabout 0.5% by weight ethyl octadecatetraenoate, about 0.05% to about0.25% by weight ethyl nonadecapentaenoate, about 0.2% to about 0.45% byweight ethyl arachidonate, about 0.3% to about 0.5% by weight ethyleicosatetraenoate, and about 0.05% to about 0.32% by weight ethylheneicosapentaenoate. Optionally, the composition contains not more thanabout 0.06%, about 0.05%, or about 0.04%, by weight, DHA or derivativethereof such as ethyl-DHA.

In one embodiment the composition contains substantially no or no amountof DHA or derivative thereof such as ethyl-DHA. The composition furtheroptionally comprises one or more antioxidants (e.g. tocopherol) in anamount of not more than about 0.5% or not more than 0.05%.

In another embodiment, the composition comprises about 0.05% to about0.4%, for example about 0.2% by weight tocopherol. In anotherembodiment, about 500 mg to about 1 g of the composition is provided ina capsule shell. In another embodiment, the capsule shell contains nochemically modified gelatin.

In another embodiment, a composition useful in accordance with theinvention comprises a hydroxyl compound and a fatty acid componentcomprising, consisting essentially of or consisting of at least 96% byweight ethyl eicosapentaenoate, about 0.22% to about 0.4% by weightethyl octadecatetraenoate, about 0.075% to about 0.20% by weight ethylnonadecapentaenoate, about 0.25% to about 0.40% by weight ethylarachidonate, about 0.3% to about 0.4% by weight ethyl eicosatetraenoateand about 0.075% to about 0.25% by weight ethyl heneicosapentaenoate.Optionally, the fatty acid component of the composition contains notmore than about 0.06%, about 0.05%, or about 0.04%, by weight, DHA orderivative thereof such as ethyl-DHA. In one embodiment the compositioncontains substantially no or no amount of DHA or derivative thereof suchas ethyl-DHA. The composition further optionally comprises one or moreantioxidants (e.g. tocopherol) in an amount of not more than about 0.5%or not more than 0.05%. In another embodiment, the composition comprisesabout 0.05% to about 0.4%, for example about 0.2% by weight, tocopherol.In another embodiment, the invention provides a dosage form comprisingabout 500 mg to about 1 g of the foregoing composition in a capsuleshell. In one embodiment, the dosage form is a gel- or liquid-containingcapsule and is packaged in blister packages of about 1 to about 20capsules per sheet.

In another embodiment, a composition useful in accordance with theinvention comprises a hydroxyl compound and a fatty acid componentcomprising, consisting essentially of or consisting of at least 96%, 97%or 98%, by weight, ethyl eicosapentaenoate, about 0.25% to about 0.38%by weight ethyl octadecatetraenoate, about 0.10% to about 0.15% byweight ethyl nonadecapentaenoate, about 0.25% to about 0.35% by weightethyl arachidonate, about 0.31% to about 0.38% by weight ethyleicosatetraenoate, and about 0.08% to about 0.20% by weight ethylheneicosapentaenoate. Optionally, the composition contains not more thanabout 0.06%, about 0.05%, or about 0.04%, by weight, DHA or derivativethereof such as ethyl-DHA. In one embodiment the composition containssubstantially no or no amount of DHA or derivative thereof such asethyl-DHA. The composition further optionally comprises one or moreantioxidants (e.g. tocopherol) in an amount of not more than about 0.5%or not more than 0.05%. In another embodiment, the composition comprisesabout 0.05% to about 0.4%, for example about 0.2% by weight tocopherol.In another embodiment, the invention provides a dosage form comprisingabout 500 mg to about 1 g of the foregoing composition in a capsuleshell. In another embodiment, the capsule shell contains no chemicallymodified gelatin.

In various embodiments, capsule shells suitable for use in the presentinvention comprise one or more film-forming materials, one or moreplasticizers and optionally a solvent (e.g. water). In a relatedembodiment, the film-forming material comprises gelatin. In anotherembodiment, the plasticizer comprises a hygroscopic and/ornon-hygroscopic plasticizer. In still another embodiment, the capsuleshell comprises a film-forming material, a hygroscopic plasticizer, anon-hygroscopic plasticizer and a solvent.

In another embodiment, the capsule shell comprises about 30% to about70% or about 40% to about 65%, by weight, of a film-forming material,about 15% to about 40% or about 20% to about 35%, by weight, of one ormore plasticizers, and about 3% to about 15% or about 5% to about 10%,by weight, solvent such as water. Optionally, the capsules may alsocontain additives such as colorants, flavorants, preservatives,disintegrants, surfactants, fragrances, sweeteners, etc.

Capsules suitable for use in various embodiments of the inventioncomprise a film-forming material, for example gelatin. Gelatin istypically manufactured from animal byproducts that contain collagen, forexample in the bones, skin, and connective tissue. Methods of producinggelatin from animal byproducts are well-known in the art. In variousembodiments, the gelatin may be alkali-treated gelatin, acid-treatedgelatin, chemically modified gelatin, or mixtures thereof. Methods toproduce alkali-treated gelatin, acid-treated gelatin, and chemicallymodified gelatin are known in the art and are described, for example inNakamura et al., U.S. 2003/0195246, hereby incorporated by referenceherein in its entirety.

The film-forming material may also comprise, for example, non-animalbased hydrocolloids such as carrageenan, alkylated or hydroxyalkylatedcellulose ethers, starch, alpha-starch, hydroxyalkyl starch, sodiumalginate, sodium salt of a gelatin copolymer and acrylic acid.

In another embodiment, the film-forming material can comprise a 20:80 toabout 80:20, by weight, mixture, for example a 60:40, by weight mixtureof hydroxypropyl methyl cellulose and polyvinyl alcohol (e.g. about 70%to about 90%, for example about 88.0% saponified; and about 30 to about50, for example about 45.0 centipoise viscosity). In another embodiment,the film-forming material can comprise a 20:80 to about 80:20, byweight, mixture, for example a 60:40, by weight, mixture of hydroxyethylcellulose and polyvinyl alcohol (e.g. about 70% to about 99.9%, forexample about 98.5% saponified; and about 2 to about 30, for exampleabout 5.5 centipoise viscosity).

A suitable capsule shell may further comprise an elasticity reducing gelextender as part of the film-forming material. An elasticity reducinggel extender can comprise starch, starch derivatives such as highamylose starch, oxidized starch, esterified starch, acid-thinned starch,etherified starch, hydrolyzed starch, hydrolyzed and hydrogenatedstarch, enzyme treated starch, and modified celluloses or other naturalor modified natural biopolymers such as bacterial polysaccharides,vegetable gums, or other exudates including alginates, carrageenans,guar gum, gum arabic, gum ghatti, gum karaya, gum tragacanth, pectins,tamarind gum, xanthan gum, and dextrans as well as synthetic polymerssuch as carbon chain polymers of the vinyl and acrylic types as well asheterochains of the polyoxide and polyamine types including polyethyleneoxide, polypropylene oxide, polyoxymethylene, polytrimethylene oxide,block copolymers of ethylene oxide, block copolymers of polyethyleneoxide, polyvinyl methyl ether, polyethylene imine, polyacrylic acid,polyacrylamide, polymethacrylic acid, polymethacrylamide,poly(N,N-Dimethylacrylamide), poly(N-Isopropylacrylamide),poly(N-Acrylylglycinamide), poly(N-Methyacrylyglycinamide), acryliccopolymers, polyvinyl alcohol polyvinylacetate, polyvinylacetate-co-vinyl alcohol, polyvinylpyrrolidone, N-Methylpyrrolidone,N-Ethylpyrrolidone, N-Vinylpyrrolidone, sarcosine anhydride,polyvinyloxazolindone, and polyvinylmethyloxazolidone. The starch orother elasticity reducing gel extender may be added into the formulationin amounts ranging from about 8% to about 30% by weight, for exampleabout 10% to about 16%, by weight.

Capsule shells suitable for use in various embodiments of the inventioncan comprise one or more plasticizers, for example hygroscopic and/ornon-hygroscopic plasticizers. Non-limiting examples of suitablehygroscopic plasticizers include glycerin, sorbitol and alkylene glycols(e.g., propylene glycol and low molecular weight polyethylene glycols).Non-limiting examples of suitable non-hygroscopic plasticizers includepartially dehydrated hydrogenated glucose syrup, maltitol, maltose,lactitol, xylitol, erythritol and polyethylene glycols of averagemolecular weights from about 400 to about 6000.

In one embodiment, a capsule shell suitable for use in a composition ofthe invention has a hygroscopic plasticizer to non-hygroscopicplasticizer weight ratio of about 1:1 to about 8:1, about 2:1 to about6:1, about 3:1 to about 5:1, for example about 4:1, about 4.25:1, about4.5:1 or about 4.75:1.

In another embodiment, a capsule shell suitable for use in a compositionof the invention has a gelatin to glycerol weight ratio of about 2:5:1to about 10:1, about 3.5:1 to about 9:1, about 4:1 to about 8:1, orabout 5:1 to about 7:1, for example at least about 2.6:1, at least about2.7:1, at least about 2.8:1, at least about 2.9:1, at least about 3:1,at least about 3.1:1, at least about 3.2:1, at least about 3.3:1, atleast about 3.4:1, at least about 3.5:1, at least about 3.6:1, at leastabout 3.7:1, at least about 3.8:1, at least about 3.9:1, at least about4.0:1, at least about 4.1:1, at least about 4.2:1, at least about 4.3:1,at least about 4.4:1, at least about 4.5:1, at least about 4.6:1, atleast about 4.7:1, at least about 4.8:1, at least about 4.9:1, at leastabout 5.0:1, at least about 5.1:1, or at least about 5.2:1.

In another embodiment, a suitable capsule shell has a film-formingmaterial (e.g. gelatin) to total plasticizer weight ratio of about 1.75to about 5, about 1.78 to about 3, or about 1.8 to about 2.5, forexample at least about 1.76, at least about 1.77, at least about 1.78,at least about 1.79, at least about 1.8, at least about 1.81, at leastabout 1.82, at least about 1.83, or at least about 1.84.

In another embodiment, the capsule shell has: (1) a gelatin to glycerolweight ratio of about 2:5:1 to about 10:1, about 3.5:1 to about 9:1,about 4:1 to about 8:1, or about 5:1 to about 7:1, for example at leastabout 2.6:1, at least about 2.7:1, at least about 2.8:1, at least about2.9:1, at least about 3:1, at least about 3.1:1, at least about 3.2:1,at least about 3.3:1, at least about 3.4:1, at least about 3.5:1, atleast about 3.6:1, at least about 3.7:1, at least about 3.8:1, at leastabout 3.9:1, at least about 4.0:1, at least about 4.1:1, at least about4.2:1, at least about 4.3:1, at least about 4.4:1, at least about 4.5:1,at least about 4.6:1, at least about 4.7:1, at least about 4.8:1, atleast about 4.9:1, at least about 5.0:1, at least about 5.1:1, or atleast about 5.2:1; and/or (2) a gelatin to total plasticizer weightratio of about 1.75:1 to about 5:1, about 1.78:1 to about 3:1, or about1.8:1 to about 2.5:1, for example at least about 1.76:1, at least about1.77:1, at least about 1.78:1, at least about 1.79:1, at least about1.8:1, at least about 1.81, at least about 1.82, at least about 1.83, orat least about 1.84.

In one embodiment, the capsule shell comprises one or more of: gelatinin an amount of about 50% to about 70%; glycerol in an amount of about5% to about 15%; sorbitol in an amount of about 15% to about 25%; and/ormaltitol in an amount of about 3% to about 10%, by weight of thenon-aqueous components. Such a capsule can further comprise about 2% toabout 16% by weight of a solvent such as water.

In another embodiment, a capsule shell suitable for use in compositionsof the present invention can be prepared using a gel mass comprisingabout 40% to about 50% gelatin, about 2% to about 12% glycerol, about10% to about 20% sorbitol solution, about 2% to about 10% maltitolsyrup, and about 20% to about 35% water, by weight. In one embodiment, acapsule shell suitable for us in a composition of the present inventioncan be prepared using a gel mass comprising about 45% gelatin by weight,about 7% glycerol by weight, about 17% sorbitol solution (e.g. 30%water) by weight, about 6% maltitol syrup (e.g. 15%-32% water) byweight, and about 25% water by weight. Capsules prepared from such a gelmass can be dried to about 2% to about 12% final moisture content.Capsules prepared by such a process that contain EPA (e.g. E-EPA orultra pure E-EPA), and methods of using the same in the treatment ofcardiovascular-related diseases represent further embodiments of theinvention. Capsule compositions as described herein can further comprisecoatings, for example enteric polymer or wax coatings.

The film formers are applied from a solvent system containing one ormore solvents including water, alcohols like methyl alcohol, ethylalcohol or isopropyl alcohol, ketones like acetone, or ethylmethylketone, chlorinated hydrocarbons like methylene chloride,dichloroethane, and 1,1,1-trichloroethane.

In some embodiments, the present invention provides a dosage formcomprising a fill comprising a hydroxyl compound and a fatty acidcomponent comprising at least about 80%, by weight of all fatty acids(and/or derivatives thereof) present, ethyl eicosapentaenoate. In someembodiments, the dosage form comprises at least about 90%, by weight ofall fatty acids (and/or derivatives thereof) present, ethyleicosapentaenoate. In some embodiments, the dosage form comprises atleast about 80%, by weight of all fatty acids (and/or derivativesthereof) present, ethyl eicosapentaenoate. In some embodiments, thedosage form comprises at least about 90%, by weight of all fatty acids(and/or derivatives thereof) present, ethyl eicosapentaenoate. In someembodiments, the dosage form comprises at least about 95%, by weight ofall fatty acids (and/or derivatives thereof) present, ethyleicosapentaenoate. In some embodiments, the dosage form comprises atleast about 96%, by weight of all fatty acids (and/or derivativesthereof) present, ethyl eicosapentaenoate. In some embodiments, thedosage form comprises no more than about 4%, by weight of all fattyacids (and/or derivatives thereof) present, docosahexaenoic acid orester thereof. In some embodiments, the dosage form comprises no morethan about 1%, by weight of all fatty acids (and/or derivatives thereof)present, of any single fatty acid other than ethyl eicosapentaenoate. Insome embodiments, the hydroxyl compound is present in an amount of about2 mg to about 1000 mg, about 5 mg to about 500 mg, about 7 mg to about200 mg, about 10 mg to about 100 mg, about 7 mg to about 10 mg, about 2mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about7.1 mg, about 7.2 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg,about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 20 mg, about25 mg, about 28 mg, about 30 mg, about 35 mg, about 40 mg, about 42 mg,about 45 mg, about 49 mg, about 50 mg, about 55 mg, about 56 mg, about60 mg, about 63 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about185 mg, about 190 mg, about 195 mg, or about 200 mg. In someembodiments, the ethyl eicosapentaenoate is present in an amount ofabout 400 mg to about 2400 mg, about 400 mg to about 600 mg, about 800mg to about 1200 mg, or about 1600 mg to about 2400 mg. In someembodiments, the hydroxyl compound is present in an amount of about 2 mgto about 10 mg and the ethyl eicosapentaenoate is present in an amountof about 400 mg to about 2400 mg. In some embodiments, the compositionhas a peroxide value not greater than 8 meq/kg upon storage of thecomposition at 25° C. and 60% RH for a period of 6 months.

In some embodiments, the hydroxyl compound is present as a component ofthe capsule contents, for example as a solid dosage form (e.g., tablet,pill, capsule, powder, bead, microbead, crystal, paste, or any othersuitable solid or semisolid form) mixed with the ethyleicosapentaenoate, surrounded by the ethyl eicosapentaenoate, dispersedin the ethyl eicosapentaenoate, or suspended in the ethyleicosapentaenoate. In some embodiments, the hydroxyl compound is atablet (e.g., an immediate release tablet, an extended release a tablet,control release tablet, etc.) suspended in the ethyl eicosapentaenoatewithin a capsule shell. In some embodiments, the hydroxyl compound is apill suspended in the ethyl eicosapentaenoate within a capsule shell.

In some embodiments, the present invention provides a dosage formcomprising a capsule shell and a fill comprising a hydroxyl compound andat least about 80%, at least about 90%, at least about 95%, or at leastabout 96%, by weight of all fatty acids (and/or derivatives thereof)present, ethyl eicosapentaenoate. In some embodiments, the capsule shellcomprises gelatin, such as a soft gelatin. In some embodiments, thehydroxyl compound is suspended in the ethyl eicosapentaenoate. In someembodiments, the hydroxyl compound is in the form of a solid dosageform, such as a tablet. In some embodiments, the dosage form comprisesno more than about 20%%, no more than about 10%, no more than about 5%,no more than about 4%, no more than about 3%, no more than about 2%, orno more than about 1%, by weight of all fatty acids (and/or derivativesthereof) present, docosahexaenoic acid or ester thereof. In someembodiments, the dosage form comprises no more than about 1%, by weightof all fatty acids (and/or derivatives thereof) present, of any singlefatty acid other than ethyl eicosapentaenoate. In some embodiments, thehydroxyl compound is present in an amount of about 5 mg to about 1000mg, about 50 mg to about 500 mg, about 100 mg to about 400 mg, about 150mg to about 350 mg, about 200 mg to about 300 mg, about 25 mg, about 50mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.In some embodiments, the ethyl eicosapentaenoate is present in an amountof about 400 mg to about 2400 mg, about 400 mg to about 600 mg, about800 mg to about 1200 mg, or about 1600 mg to about 2400 mg. In someembodiments, the composition has a peroxide value not greater than 8meq/kg upon storage of the composition at 25° C. and 60% RH for a periodof 6 months.

In some embodiments, the present invention provides a capsule comprisinga hydroxyl compound in an amount of about 2 mg to about 1000 mg andabout 800 mg to about 1200 mg of a composition comprising at least about80%, by weight of all fatty acids (and/or derivatives thereof) present,ethyl eicosapentaenoate, wherein the hydroxyl compound is suspended inthe composition or is present in a coating on an exterior surface of thecapsule. In some embodiments, the hydroxyl compound is suspended in thecomposition. In some embodiments, the hydroxyl compound is in the formof a solid dosage form. In some embodiments, the hydroxyl compound is inthe form of a tablet.

In various embodiments, the invention provides a polyunsaturated fattyacid such as EPA (e.g. E-EPA or ultra pure E-EPA) encapsulated in apharmaceutical capsule shell. In one embodiment, the capsule shellresists, hinders, attenuates, or prevents oxidation of the fatty acid orfatty acid derivative. In another embodiment, the capsule shell resists,hinders, attenuates, or prevents oxidation of the polyunsaturated fattyacid or derivative to a greater extent than a standard type Ha gelatincapsule. In another embodiment, the capsule contains no chemicallymodified gelatin, for example succinated, succinylated, pthalated,carbonylated and/or phenol carbonylated gelatin.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and a fatty acid componentcomprising EPA (e.g. ethyl EPA) encapsulated in a capsule shell asdescribed herein and having a baseline peroxide value not greater thanabout 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7 meq/kg, about 6meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kg or about 2meq/kg, wherein upon storage of the composition at 23° C. and 50% RH fora period about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 7 months, about 8 months, about 9months, about 10 months, about 11 months, about 12 months, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months or about 24 months, thecomposition has a second peroxide value not greater than about 25meq/kg, about 24 meq/kg, about 23 meq/kg, about 22 meq/kg, about 21meq/kg, about 20 meq/kg, about 19 meq/kg, about 18 meq/kg, about 17meq/kg, about 16 meq/kg, about 15 meq/kg, about 14 meq/kg, about 13meq/kg, about 12 meq/kg, about 11 meq/kg, about 10 meq/kg, about 9meq/kg, about 8 meq/kg, about 7 meq/kg, about 6 meq/kg, about 5 meq/kg,about 4 meq/kg, about 3 meq/kg or about 2 meq/kg.

The “baseline peroxide value” and “second peroxide values” can bemeasured in any suitable manner, for example by using a U.S. or PhEur orJP compendial method. Typically, a plurality of encapsulated EPAcompositions are provided, each composition containing EPA having beenencapsulated at substantially the same time. A first sampling of 1 ormore capsules from the plurality is provided, the capsules are openedand peroxide value of the EPA is measured substantially immediatelythereafter, providing an average baseline peroxide value. Atsubstantially the same time, a second sampling of 1 or more capsulesfrom the plurality are provided and are placed under desired storageconditions for a desired time period. At the end of the desired timeperiod, the capsules are opened and peroxide value of the EPA ismeasured substantially immediately thereafter, providing an averagesecond peroxide value. The baseline and second peroxide values can thenbe compared. In one embodiment, the “baseline peroxide value” and“second peroxide value” are determined using a plurality of encapsulatedEPA dosage units wherein each dosage unit was encapsulated (i.e. the EPAfilled and sealed into capsules) within a same 60 day period, same 30day period, a same 20 day period, a same 10 day period, a same 5 dayperiod or a same 1 day period.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and a fatty acid componentcomprising EPA (e.g. ethyl EPA) encapsulated in a capsule shell asdescribed herein and having a baseline peroxide value not greater thanabout 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7 meq/kg, about 6meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kg or about 2meq/kg, wherein upon storage of the composition at 25° C. and 60% RH fora period about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 7 months, about 8 months, about 9months, about 10 months, about 11 months, about 12 months, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months or about 24 months, saidcomposition has a second peroxide value not greater than about 25meq/kg, about 24 meq/kg, about 23 meq/kg, about 22 meq/kg, about 21meq/kg, about 20 meq/kg, about 19 meq/kg, about 18 meq/kg, about 17meq/kg, about 16 meq/kg, about 15 meq/kg, about 14 meq/kg, about 13meq/kg, about 12 meq/kg, about 11 meq/kg, about 10 meq/kg, about 9meq/kg, about 8 meq/kg, about 7 meq/kg, about 6 meq/kg, about 5 meq/kg,about 4 meq/kg, about 3 meq/kg or about 2 meq/kg.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and EPA (e.g. ethyl EPA)encapsulated in a capsule shell as described herein and having abaseline peroxide value not greater than about 10 meq/kg, about 9meq/kg, about 8 meq/kg, about 7 meq/kg, about 6 meq/kg, about 5 meq/kg,about 4 meq/kg, about 3 meq/kg or about 2 meq/kg, wherein upon storageof the composition at 30° C. and 65% RH for a period about 1 month,about 2 months, about 3 months, about 4 months, about 5 months, about 6months, about 7 months, about 8 months, about 9 months, about 10 months,about 11 months, about 12 months, about 13 months, about 14 months,about 15 months, about 16 months, about 17 months, about 18 months,about 19 months, about 20 months, about 21 months, about 22 months,about 23 months or about 24 months, said composition has a secondperoxide value not greater than about 25 meq/kg, about 24 meq/kg, about23 meq/kg, about 22 meq/kg, about 21 meq/kg, about 20 meq/kg, about 19meq/kg, about 18 meq/kg, about 17 meq/kg, about 16 meq/kg, about 15meq/kg, about 14 meq/kg, about 13 meq/kg, about 12 meq/k meq/kg g, about11 meq/kg, about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and EPA (e.g. ethyl EPA)encapsulated in a capsule shell as described herein and having abaseline peroxide value not greater than about 10 meq/kg, about 9meq/kg, about 8 meq/kg, about 7 meq/kg, about 6 meq/kg, about 5 meq/kg,about 4 meq/kg, about 3 meq/kg or about 2 meq/kg, wherein upon storageof the composition at 40° C. and 75% RH for a period about 1 month,about 2 months, about 3 months, about 4 months, about 5 months, about 6months, about 7 months, about 8 months, about 9 months, about 10 months,about 11 months, about 12 months, about 13 months, about 14 months,about 15 months, about 16 months, about 17 months, about 18 months,about 19 months, about 20 months, about 21 months, about 22 months,about 23 months or about 24 months, said composition has a secondperoxide value not greater than about 25 meq/kg, about 24 meq/kg, about23 meq/kg, about 22 meq/kg, about 21 meq/kg, about 20 meq/kg, about 19meq/kg, about 18 meq/kg, about 17 meq/kg, about 16 meq/kg, about 15meq/kg, about 14 meq/kg, about 13 meq/kg, about 12 meq/kg, about 11meq/kg, about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7 meq/kg,about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kg or about2 meq/kg.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and EPA (e.g. ethyl EPA)encapsulated in a capsule shell and having a baseline peroxide value notgreater than about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg, wherein the capsule comprises a film-forming materialand a plasticizer in a weight ratio of not less than 1.75:1 and whereinupon storage of the composition at 23° C. and 50% RH for a period about1 month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, said composition has asecond peroxide value not greater than about 25 meq/kg, about 24 meq/kg,about 23 meq/kg, about 22 meq/kg, about 21 meq/kg, about 20 meq/kg,about 19 meq/kg, about 18 meq/kg, about 17 meq/kg, about 16 meq/kg,about 15 meq/kg, about 14 meq/kg, about 13 meq/kg, about 12 meq/kg,about 11 meq/kg, about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about7 meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and EPA (e.g. ethyl EPA)encapsulated in a capsule shell and having a baseline peroxide value notgreater than about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg, wherein the capsule comprises a film-forming materialand a plasticizer in a weight ratio of not less than 1.75:1 and whereinupon storage of the composition at 25° C. and 60% RH for a period about1 month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, said composition has asecond peroxide value not greater than about 25 meq/kg, about 24 meq/kg,about 23 meq/kg, about 22 meq/kg, about 21 meq/kg, about 20 meq/kg,about 19 meq/kg, about 18 meq/kg, about 17 meq/kg, about 16 meq/kg,about 15 meq/kg, about 14 meq/kg, about 13 meq/kg, about 12 meq/kg,about 11 meq/kg, about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about7 meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and EPA (e.g. ethyl EPA)encapsulated in a capsule shell and having a baseline peroxide value notgreater than about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg, wherein the capsule comprises a film-forming materialand a plasticizer in a weight ratio of not less than 1.75:1 and whereinupon storage of the composition at 30° C. and 65% RH for a period about1 month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, said composition has asecond peroxide value not greater than about 25 meq/kg, about 24 meq/kg,about 23 meq/kg, about 22 meq/kg, about 21 meq/kg, about 20 meq/kg,about 19 meq/kg, about 18 meq/kg, about 17 meq/kg, about 16 meq/kg,about 15 meq/kg, about 14 meq/kg, about 13 meq/kg, about 12 meq/kg,about 11 meq/kg, about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about7 meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and EPA (e.g. ethyl EPA)encapsulated in a capsule shell and having a baseline peroxide value notgreater than about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg, wherein the capsule comprises a film-forming materialand a plasticizer in a weight ratio of not less than 1.75:1 and whereinupon storage of the composition at 40° C. and 75% RH for a period about1 month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, said composition has asecond peroxide value not greater than about 25 meq/kg, about 24 meq/kg,about 23 meq/kg, about 22 meq/kg, about 21 meq/kg, about 20 meq/kg,about 19 meq/kg, about 18 meq/kg, about 17 meq/kg, about 16 meq/kg,about 15 meq/kg, about 14 meq/kg, about 13 meq/kg, about 12 meq/kg,about 11 meq/kg, about 10 meq/kg, about 9 meq/kg, about 8 meq/kg, about7 meq/kg, about 6 meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kgor about 2 meq/kg.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount (i.e. initial amount) of EPA orE-EPA, wherein upon storage of the composition at 23° C. and 50% RH fora period about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 7 months, about 8 months, about 9months, about 10 months, about 11 months, about 12 months, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months or about 24 months, saidcomposition contains at least about 97%, about 98%, about 99%, about99.5%, about 99.7%, about 99.9% or substantially all or 100% of thelabeled amount of EPA or E-EPA, by weight.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount (i.e. initial amount) of EPA orE-EPA, wherein upon storage of the composition at 25° C. and 60% RH fora period about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 7 months, about 8 months, about 9months, about 10 months, about 11 months, about 12 months, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months or about 24 months, saidcomposition contains at least about 97%, about 98%, about 99%, about99.5%, about 99.7%, about 99.9% or substantially all or 100% of thelabeled amount of EPA or E-EPA, by weight.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein uponstorage of the composition at 30° C. and 65% RH for a period about 1month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, said composition contains atleast about 97%, about 98%, about 99%, about 99.5%, about 99.7%, about99.9%, substantially all or 100% of the labeled amount of EPA or E-EPA,by weight.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA, wherein upon storage ofthe composition at 40° C. and 75% RH for a period about 1 month, about 2months, about 3 months, about 4 months, about 5 months, about 6 months,about 7 months, about 8 months, about 9 months, about 10 months, about11 months, about 12 months, about 13 months, about 14 months, about 15months, about 16 months, about 17 months, about 18 months, about 19months, about 20 months, about 21 months, about 22 months, about 23months or about 24 months, said composition contains at least about 97%,about 98%, about 99%, about 99.5%, about 99.7%, about 99.8%, about99.9%, substantially all or 100% of the labeled amount of EPA or E-EPA,by weight.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein uponstorage of the composition at 23° C. and 50% RH for a period about 1month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, said composition containsnot more than about 0.5%, not more than about 0.25%, not more than about0.15%, not more than about 0.125%, not more than about 0.1%, not morethan about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product. The term“degradation product” in the present context means “an impurityresulting from a chemical change in the composition brought about duringmanufacture and/or storage of the composition by the effect of, forexample, light, temperature, pH, water or by reaction with an excipientand/or the immediate container closure system.” The term “specifieddegradation product in the present context means “a degradation product,either identified or unidentified, that is individually listed andlimited with a specific acceptance criterion in the productspecification” for a particular product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein uponstorage of the composition at 25° C. and 60% RH for a period about 1month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, the composition contains notmore than about 0.5%, not more than about 0.25%, not more than about0.15%, not more than about 0.125%, not more than about 0.1%, not morethan about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein uponstorage of the composition at 30° C. and 65% RH for a period about 1month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, the composition contains notmore than about 0.5% (by weight of the labeled EPA or E-EPA), not morethan about 0.25%, not more than about 0.15%, not more than about 0.125%,not more than about 0.1%, not more than about 0.075%, not more thanabout 0.05% or substantially no degradation product and/or specifieddegradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein uponstorage of the composition at 40° C. and 75% RH for a period about 1month, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 7 months, about 8 months, about 9 months, about 10months, about 11 months, about 12 months, about 13 months, about 14months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22months, about 23 months or about 24 months, the composition contains notmore than about 0.5% (by weight of the labeled EPA or E-EPA), not morethan about 0.25%, not more than about 0.15%, not more than about 0.125%,not more than about 0.1%, not more than about 0.075%, not more thanabout 0.05% or substantially no degradation product and/or specifieddegradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein thecapsule comprises a film-forming material, a hygroscopic plasticizer anda non-hygroscopic plasticizer and upon storage of the composition at 23°C. and 50% RH for a period about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 7 months,about 8 months, about 9 months, about 10 months, about 11 months, about12 months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, the composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA, wherein the capsulecomprises a film-forming material, a hygroscopic plasticizer and anon-hygroscopic plasticizer and upon storage of the composition at 25°C. and 60% RH for a period about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 7 months,about 8 months, about 9 months, about 10 months, about 11 months, about12 months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, the composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA, wherein the capsulecomprises a film-forming material, a hygroscopic plasticizer and anon-hygroscopic plasticizer and upon storage of the composition at 30°C. and 65% RH for a period about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 7 months,about 8 months, about 9 months, about 10 months, about 11 months, about12 months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, the composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and EPA (e.g. ethyl EPA)containing a labeled amount of EPA or E-EPA, wherein the capsulecomprises a film-forming material, a hygroscopic plasticizer and anon-hygroscopic plasticizer and upon storage of the composition at 40°C. and 75% RH for a period about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 7 months,about 8 months, about 9 months, about 10 months, about 11 months, about12 months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, the composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein thecapsule comprises a film-forming material and a plasticizer in a weightratio of about 2:5:1 to about 10:1 and upon storage of the compositionat 23° C. and 50% RH for a period about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 7 months,about 8 months, about 9 months, about 10 months, about 11 months, about12 months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, the composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA, wherein the capsulecomprises a film-forming material and a plasticizer in a weight ratio ofabout 2:5:1 to about 10:1 and upon storage of the composition at 25° C.and 60% RH for a period about 1 month, about 2 months, about 3 months,about 4 months, about 5 months, about 6 months, about 7 months, about 8months, about 9 months, about 10 months, about 11 months, about 12months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, said composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein thecapsule comprises a film-forming material and a plasticizer in a weightratio of about 2:5:1 to about 10:1 and upon storage of the compositionat 30° C. and 65% RH for a period about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 7 months,about 8 months, about 9 months, about 10 months, about 11 months, about12 months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, said composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising an encapsulated hydroxyl compound and EPA (e.g.ethyl EPA) containing a labeled amount of EPA or E-EPA, wherein thecapsule comprises a film-forming material and a plasticizer in a weightratio of about 2:5:1 to about 10:1 and upon storage of the compositionat 40° C. and 75% RH for a period about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 7 months,about 8 months, about 9 months, about 10 months, about 11 months, about12 months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, said composition contains not more than about 0.5% (by weight ofthe labeled EPA or E-EPA), not more than about 0.25%, not more thanabout 0.15%, not more than about 0.125%, not more than about 0.1%, notmore than about 0.075%, not more than about 0.05% or substantially nodegradation product and/or specified degradation product.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a hydroxyl compound and about 0.5 g to about 1.5g of EPA (e.g. E-EPA or ultra pure E-EPA) having a labeled amount of EPAor E-EPA encapsulated in a pharmaceutical capsule, wherein upon storageat 15° C. to 30° C. for a period of about 6 months, about 12 months,about 18 months, about 24 months, about 30 months, or about 36 months,at least about 97%, about 98%, about 99%, about 99.5%, about 99.6%,about 99.7%, about 99.8%, about 99.9% or substantially all of thelabeled amount of EPA is still present in the composition. In a relatedembodiment, the composition has not reached its labeled expiration dateduring said storage period.

In one embodiment, a composition of the invention provides a relativelyrapid dissolution profile yet still maintains excellent stability of theencapsulated material (e.g. EPA). In a related embodiment, a compositionof the invention has a dissolution profile (as measured by RotatingDialysis Cell Dissolution (RDC) Apparatus under the conditions set forthherein below) of one or more of the following: (1) at least about 20%,at least about 23% or at least about 25% of E-EPA is dissolved by 10minutes; (2) at least about 45%, at least about 50% or at least about55% of E-EPA is dissolved by 30 minutes; (3) at least about 80%, atleast about 82%, at least about 85% or at least about 87% of E-EPA isdissolved by 60 minutes; and/or (4) at least about 95%, at least about97% or 100% of E-EPA is dissolved by 100 minutes. In a relatedembodiment, the fill material still retains the stability/peroxidevalues as set forth throughout this specification.

In another embodiment, a composition of the invention provides arelatively short T_(max) yet still maintains excellent stability of theencapsulated material (e.g. EPA). In a related embodiment, a compositionof the invention, upon administration to a subject, exhibits an EPAT_(max) less than 6 hours, less than 5.8 hours, less than 5.6 hours,less than 5.4 hours or less than 5.2 hours, for example about 4.8 toabout 5.2 hours. In a related embodiment, the fill material stillretains the stability/peroxide values as set forth throughout thisspecification.

In one embodiment, a method for treatment and/or prevention of acardiovascular-related disease using a composition as described hereinis provided. The term “cardiovascular-related disease” herein refers toany disease or disorder of the heart or blood vessels (i.e. arteries andveins) or any symptom thereof. The term “cardiovascular-related disease”herein refers to any disease or disorder of the heart or blood vessels(i.e. arteries and veins) or any symptom thereof, or any disease orcondition that causes or contributes to a cardiovascular disease.”Non-limiting examples of cardiovascular-related diseases include acutecardiac ischemic events, acute myocardial infarction, angina, anginapectoris, arrhythmia, atrial fibrulation, atherosclerosis, arterialfibrillation, cardiac insufficiency, cardiovascular disease, chronicheart failure, chronic stable angina, congestive heart failure, coronaryartery disease, coronary heart disease, deep vein thrombosis, diabetes,diabetes mellitus, diabetic neuropathy, diastolic dysfunction insubjects with diabetes mellitus, edema, essential hypertension, eventualpulmonary embolism, fatty liver disease, heart disease, heart failure,homozygous familial hypercholesterolemia (HoFH), homozygous familialsitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia inHIV positive subjects, hypertension, hypertriglyceridemia, ischemiccomplications in unstable angina and myocardial infarction, low bloodpressure, metabolic syndrome, mixed dyslipidemia, moderate to mild heartfailure, myocardial infarction, obesity management, paroxysmalatrial/arterial fibrillation/fibrulation/flutter, paroxysmalsupraventricular tachycardias (PSVT), particularly severe or rapid onsetedema, platelet aggregation, primary hypercholesterolemia, primaryhyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension,recurrent hemodynamically unstable ventricular tachycardia (VT),recurrent ventricular arrhythmias, recurrent ventricular fibrillation(VF), ruptured aneurysm, sitisterolemia, stroke, supraventriculartachycardia, symptomatic atrial fibrillation/flutter, tachycardia,type-II diabetes, vascular disease, venous thromboembolism, ventriculararrhythmias, and other cardiovascular events.

The term “treatment” in relation a given disease or disorder, includes,but is not limited to, inhibiting the disease or disorder, for example,arresting the development of the disease or disorder; relieving thedisease or disorder, for example, causing regression of the disease ordisorder; or relieving a condition caused by or resulting from thedisease or disorder, for example, relieving, preventing or treatingsymptoms of the disease or disorder. The term “prevention” in relationto a given disease or disorder means: preventing the onset of diseasedevelopment if none had occurred, preventing the disease or disorderfrom occurring in a subject that may be predisposed to the disorder ordisease but has not yet been diagnosed as having the disorder ordisease, and/or preventing further disease/disorder development ifalready present.

In some embodiments, compositions of the present invention can beco-administered or administered concomitantly. The terms“co-administered,” “concomitant administration,” and “administeredconcomitantly” are used interchangeably herein and each refer to, forexample, administration of two or more agents (e.g., EPA or a derivativethereof and a hydroxyl compound) at the same time, in the same dosageunit, one immediately after the other, within five minutes of eachother, within ten minutes of each other, within fifteen minutes of eachother, within thirty minutes of each other, within one hour of eachother, within two hours of each other, within four hours of each other,within six hours of each other, within twelve hours of each other,within one day of each other, within one week of each other, within twoweeks of each other, within one month of each other, within two monthsof each other, within six months of each other, within one year of eachother, etc.

In one embodiment, the present invention provides a method of treating acardiovascular-related disease comprising co-administering to a subjectin need thereof a composition or compositions comprising EPA and ahydroxyl compound (either as a single dosage unit or as multiple dosageunits). In some embodiments, one or more lipid parameters are improvedby comparison with lipid parameters achieved by the additive effects ofthe individual treatments.

In one embodiment, the present invention provides a method of bloodlipid therapy comprising administering to a subject or subject group inneed thereof a pharmaceutical composition as described herein. Inanother embodiment, the subject or subject group hashypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/orvery high triglycerides.

In another embodiment, the subject or subject group being treated has abaseline triglyceride level (or median baseline triglyceride level inthe case of a subject group), fed or fasting, of at least about 200mg/dl, at least about 300 mg/dl, at least about 400 mg/dl, at leastabout 500 mg/dl, at least about 600 mg/dl, at least about 700 mg/dl, atleast about 800 mg/dl, at least about 900 mg/dl, at least about 1000mg/dl, at least about 1100 mg/dl, at least about 1200 mg/dl, at leastabout 1300 mg/dl, at least about 1400 mg/dl, or at least about 1500mg/dl, for example about 400 mg/dl to about 2500 mg/dl, about 450 mg/dlto about 2000 mg/dl or about 500 mg/dl to about 1500 mg/dl.

In a related embodiment, upon treatment in accordance with the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits one or more of the following outcomes:

(a) reduced triglyceride levels compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(b) reduced Apo B levels compared to baseline, to placebo control, to asecond subject who has received a hydroxyl compound but not EPA, or to asecond subject who has received EPA but not a hydroxyl compound;

(c) increased HDL-C levels compared to baseline, to placebo control, toa second subject who has received a hydroxyl compound but not EPA, or toa second subject who has received EPA but not a hydroxyl compound;

(d) no increase in LDL-C levels compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(e) a reduction in LDL-C levels compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(f) a reduction in non-HDL-C levels compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(g) a reduction in vLDL levels compared to baseline, to placebo control,to a second subject who has received a hydroxyl compound but not EPA, orto a second subject who has received EPA but not a hydroxyl compound;

(h) an increase in apo A-I levels compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(i) an increase in apo A-I/apo B ratio compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(j) a reduction in lipoprotein A levels compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(k) a reduction in LDL particle number compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(l) an increase in LDL size compared to baseline, to placebo control, toa second subject who has received a hydroxyl compound but not EPA, or toa second subject who has received EPA but not a hydroxyl compound;

(m) a reduction in remnant-like particle cholesterol compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(n) a reduction in oxidized LDL compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(o) no change or a reduction in fasting plasma glucose (FPG) compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(p) a reduction in hemoglobin A_(1c) (HbA_(1c)) compared to baseline, toplacebo control, to a second subject who has received a hydroxylcompound but not EPA, or to a second subject who has received EPA butnot a hydroxyl compound;

(q) a reduction in homeostasis model insulin resistance compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(r) a reduction in lipoprotein associated phospholipase A2 compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(s) a reduction in intracellular adhesion molecule-1 compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(t) a reduction in interleukin-6 compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(u) a reduction in plasminogen activator inhibitor-1 compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(v) a reduction in high sensitivity C-reactive protein (hsCRP) comparedto baseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(w) an increase in serum or plasma EPA compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(x) an increase in red blood cell (RBC) membrane EPA compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(y) a reduction or increase in one or more of serum phospholipid and/orred blood cell content of docosahexaenoic acid (DHA), docosapentaenoicacid (DPA), arachidonic acid (AA), palmitic acid (PA), staeridonic acid(SA) or oleic acid (OA) compared to baseline, to placebo control, to asecond subject who has received a hydroxyl compound but not EPA, or to asecond subject who has received EPA but not a hydroxyl compound; and/or

(z) a reduction in one or more protein components of VLDL such asapolipoprotein C-III (hereinafter “APOC3”; also referred to as APOCIIIor HALP2) compared to baseline, to placebo control, to a second subjectwho has received a hydroxyl compound but not EPA, or to a second subjectwho has received EPA but not a hydroxyl compound.

In one embodiment, upon administering a composition of the invention toa subject, the subject exhibits a decrease in triglyceride levels, anincrease in the concentrations of EPA and DPA (n-3) in red blood cells,and an increase of the ratio of EPA:arachidonic acid in red blood cells.In a related embodiment the subject exhibits substantially no or noincrease in RBC DHA.

In one embodiment, methods of the present invention comprise measuringbaseline levels of one or more markers set forth in (a)-(z) above priorto dosing the subject or subject group. In another embodiment, themethods comprise administering a composition as disclosed herein to thesubject after baseline levels of one or more markers set forth in(a)-(z) are determined, and subsequently taking an additionalmeasurement of said one or more markers.

In another embodiment, upon treatment with a composition of the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits any 2 or more of, any 3 or more of,any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of,any 8 or more of, any 9 or more of, any 10 or more of, any 11 or moreof, any 12 or more of, any 13 or more of, any 14 or more of, any 15 ormore of, any 16 or more of, any 17 or more of, any 18 or more of, any 19or more of, any 20 or more of, any 21 or more of, any 22 or more of, any23 or more of, any 24 or more of, any 25 or more of, or all 26 ofoutcomes (a)-(z) described immediately above.

In another embodiment, upon treatment with a composition of the presentinvention, the subject or subject group exhibits one or more of thefollowing outcomes:

(a) a reduction in triglyceride level of at least about 4.8%, at leastabout 5%, at least about 8.7%, at least about 8.8%, at least about 10%,at least about 14.3%, at least about 14.8%, at least about 15%, at leastabout 17.5%, at least about 18.4%, at least about 20%, at least about25%, at least about 26.2%, at least about 28.9%, at least about 30%, atleast about 32.7%, at least about 35%, at least about 35.2%, at leastabout 36.0%, at least about 40%, at least about 45%, at least about48.1%, at least about 50%, at least about 55% or at least about 75%(actual % change, mean % change or median % change) as compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(b) a less than 30% increase, less than 20% increase, less than 10%increase, less than 5% increase or no increase in non-HDL-C levels or areduction in non-HDL-C levels of at least about 1%, at least about 3%,at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 21.6%, at least about 24.2%, at least about24.5%, at least about 25%, at least about 25.1%, at least about 28.8%,at least about 30%, at least about 34.0%, at least about 35%, at leastabout 37.5%, at least about 38.7%, at least about 40%, at least about45%, at least about 48.2%, at least about 50%, at least about 54.0%, atleast about 55%, at least about 71.4%, at least about 75%, at leastabout 80%, at least about 81.1%, at least about 81.3%, at least about87.7%, or at least about 90% (actual % change, mean % change or median %change) as compared to baseline, to placebo control, to a second subjectwho has received a hydroxyl compound but not EPA, or to a second subjectwho has received EPA but not a hydroxyl compound;

(c) substantially no change in HDL-C levels, no change in HDL-C levels,or an increase in HDL-C levels of at least about 2.2%, at least about2.5%, at least about 2.6%, at least about 3.3%, at least about 5%, atleast about 5.8%, at least about 10%, at least about 10.7%, at leastabout 11.7%, at least about 14.8%, at least about 15%, at least about20%, at least about 25%, at least about 27.0%, at least about 30%, atleast about 35%, at least about 40%, at least about 45%, at least about50%, at least about 55% or at least about 75% (actual % change, mean %change or median % change) as compared to baseline, to placebo control,to a second subject who has received a hydroxyl compound but not EPA, orto a second subject who has received EPA but not a hydroxyl compound;

(d) a less than 60% increase, a less than 50% increase, a less than 40%increase, a less than 30% increase, less than 20% increase, less than10% increase, less than 5% increase or no increase in LDL-C levels or areduction in LDL-C levels of at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 21.4%, at leastabout 24.7%, at least about 25%, at least about 28%, at least about 30%,at least about 32.4%, at least about 33.2%, at least about 35%, at leastabout 35.9%, at least about 26.9%, at least about 40%, at least about45%, at least about 48.4%, at least about 50%, at least about 55%, atleast about 55%, at least about 75%, at least about 80%, or at leastabout 82% (actual % change, mean % change or median % change) ascompared to baseline, to placebo control, to a second subject who hasreceived a hydroxyl compound but not EPA, or to a second subject who hasreceived EPA but not a hydroxyl compound;

(e) a decrease in Apo B levels of at least about 2.2%, at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 22.6%, at least about 24.3%, at least about 25%, at least about26.3%, at least about 26.8%, at least about 30%, at least about 33.3%,at least about 35%, at least about 35.9%, at least about 38.9% at leastabout 40%, at least about 45%, at least about 47.3%, at least about 50%,at least about 55%, at least about 73.8%, at least about 75%, at leastabout 77.1%, at least about 77.7%, at least about 87.1% (actual %change, mean % change or median % change) as compared to baseline, toplacebo control, to a second subject who has received a hydroxylcompound but not EPA, or to a second subject who has received EPA butnot a hydroxyl compound;

(f) a reduction in VLDL levels of at least about 3.0%, at least about5%, at least about 9.1%, at least about 9.4%, at least about 10%, atleast about 13.8%, at least about 15%, at least about 17.3%, at leastabout 19.6%, at least about 20%, at least about 25%, at least about26.7%, at least about 28.6%, at least about 30%, at least about 33.3%,at least about 35%, at least about 36.5%, at least about 37.1%, at leastabout 40%, at least about 45%, at least about 46.8%, at least about 50%,or at least about 100% (actual % change, mean % change or median %change) compared to baseline, to placebo control, to a second subjectwho has received a hydroxyl compound but not EPA, or to a second subjectwho has received EPA but not a hydroxyl compound;

(g) an increase in apo A-I levels of at least about 3.9%, at least about5%, at least about 9.3%, at least about 10%, at least about 15%, atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, or atleast about 100% (actual % change, mean % change or median % change)compared to baseline, to placebo control, to a second subject who hasreceived a hydroxyl compound but not EPA, or to a second subject who hasreceived EPA but not a hydroxyl compound;

(h) an increase in apo A-I/apo B ratio of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 21%,at least about 23.2%, at least about 24.0%, at least about 25%, at leastabout 26.3%, at least about 30%, at least about 30.2%, at least about31.1%, at least about 32.7% at least about 35%, at least about 37.9%, atleast about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change, mean % change or median % change) comparedto baseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(i) a reduction in lipoprotein (a) levels of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, or at least about 100% (actual % change,mean % change or median % change) compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(j) a reduction in mean LDL particle number of at least about 5%, atleast about 10%, at least about 15%, at least about 20%, at least about25%, at least about 30%, at least about 35%, at least about 40%, atleast about 45%, at least about 50%, or at least about 100% (actual %change, mean % change or median % change) compared to baseline, toplacebo control, to a second subject who has received a hydroxylcompound but not EPA, or to a second subject who has received EPA butnot a hydroxyl compound;

(k) an increase in mean LDL particle size of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, or at least about 100% (actual % change,mean % change or median % change) compared to baseline, to placebocontrol, to a second subject who has received a hydroxyl compound butnot EPA, or to a second subject who has received EPA but not a hydroxylcompound;

(l) a reduction in remnant-like particle cholesterol of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, or at least about 100% (actual %change, mean % change or median % change) compared to baseline, toplacebo control, to a second subject who has received a hydroxylcompound but not EPA, or to a second subject who has received EPA butnot a hydroxyl compound;

(m) a reduction in oxidized LDL of at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, or at least about 100% (actual % change, mean %change or median % change) compared to baseline, to placebo control, toa second subject who has received a hydroxyl compound but not EPA, or toa second subject who has received EPA but not a hydroxyl compound;

(n) substantially no change, no significant change, or a reduction (e.g.in the case of a diabetic subject) in fasting plasma glucose (FPG) of atleast about 5%, at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change, mean % change or median % change) comparedto baseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(o) substantially no change, no significant change or a reduction inhemoglobin A_(1c) (HbA_(ic)) of at least about 5%, at least about 10%,at least about 15%, at least about 20%, at least about 25%, at leastabout 30%, at least about 35%, at least about 40%, at least about 45%,or at least about 50% (actual % change, mean % change or median %change) compared to baseline, to placebo control, to a second subjectwho has received a hydroxyl compound but not EPA, or to a second subjectwho has received EPA but not a hydroxyl compound;

(p) a reduction in homeostasis model index insulin resistance of atleast about 5%, at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change, mean % change or median % change) comparedto baseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(q) a reduction in lipoprotein associated phospholipase A2 of at leastabout 5%, at least about 10%, at least about 15%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, or at least about 100%(actual % change, mean % change or median % change) compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(r) a reduction in intracellular adhesion molecule-1 of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, or at least about 100% (actual %change, mean % change or median % change) compared to baseline, toplacebo control, to a second subject who has received a hydroxylcompound but not EPA, or to a second subject who has received EPA butnot a hydroxyl compound;

(s) a reduction in interleukin-6 of at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, or at least about 100% (actual % change, mean %change or median % change) compared to baseline, to placebo control, toa second subject who has received a hydroxyl compound but not EPA, or toa second subject who has received EPA but not a hydroxyl compound;

(t) a reduction in plasminogen activator inhibitor-1 of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, or at least about 100% (actual %change, mean % change or median % change) compared to baseline, toplacebo control, to a second subject who has received a hydroxylcompound but not EPA, or to a second subject who has received EPA butnot a hydroxyl compound;

(u) a reduction in high sensitivity C-reactive protein (hsCRP) of atleast about 5%, at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change, mean % change or median % change) comparedto baseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(v) an increase in serum, plasma and/or RBC EPA of at least about 5%, atleast about 10%, at least about 15%, at least about 20%, at least about25%, at least about 30%, at least about 35%, at least about 40%, atleast about 45%, at least about 50%, at least about 100%, at least about200% or at least about 400% (actual % change, mean % change or median %change) compared to baseline, to placebo control, to a second subjectwho has received a hydroxyl compound but not EPA, or to a second subjectwho has received EPA but not a hydroxyl compound;

(w) an increase in serum phospholipid and/or red blood cell membrane EPAof at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, r at least about 50%, at leastabout 100%, at least about 200%, or at least about 400% (actual %change, mean % change or median % change) compared to baseline, toplacebo control, to a second subject who has received a hydroxylcompound but not EPA, or to a second subject who has received EPA butnot a hydroxyl compound;

(x) a reduction or increase in one or more of serum phospholipid and/orred blood cell DHA, DPA, AA, PA and/or OA of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55% or at least about 75%(actual % change, mean % change or median % change) compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound;

(y) a reduction in total cholesterol of at least about 5%, at leastabout 10%, at least about 15%, at least about 19.2%, at least about19.4%, at least about 20%, at least about 21.2%, at least about 23.3%,at least about 23.7%, at least about 25%, at least about 26.4%, at leastabout 28.3%, at least about 30%, at least about 35%, at least about39.4%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, at least about 60.7%, at least about 62.7%, at leastabout 75%, at least about 75.2%, at least about 80%, or at least about80.2% (actual % change, mean % change or median % change) compared tobaseline, to placebo control, to a second subject who has received ahydroxyl compound but not EPA, or to a second subject who has receivedEPA but not a hydroxyl compound; and/or

(z) reduction in one or more protein components of VLDL such as APOC3,of at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, at leastabout 55%, at least about 65%, at least about 70%, at least about 75%,at least about 80%, at least about 85%, at least about 90%, at leastabout 95%, at least about 100%, at least about 105%, at least about110%, at least about 115%, at least about 120%, at least about 125%, atleast about 130%, at least about 135%, at least about 140%, at leastabout 145%, at least about 150%, at least about 155%, at least about160%, at least about 165%, at least about 170%, at least about 175%, atleast about 180%, at least about 185%, at least about 190%, at leastabout 195%, or at least about 200% (actual % change, mean % change ormedian % change) compared to baseline, to placebo control, to a secondsubject who has received a hydroxyl compound but not EPA, or to a secondsubject who has received EPA but not a hydroxyl compound.

In one embodiment, methods of the present invention comprise measuringbaseline levels of one or more markers set forth in (a)-(z) prior todosing the subject or subject group.

In another embodiment, the methods comprise administering a compositionas disclosed herein to the subject after baseline levels of one or moremarkers set forth in (a)-(z) are determined, and subsequently taking asecond measurement of the one or more markers as measured at baselinefor comparison thereto.

In another embodiment, upon treatment with a composition of the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits any 2 or more of, any 3 or more of,any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of,any 8 or more of, any 9 or more of, any 10 or more of, any 11 or moreof, any 12 or more of, any 13 or more of, any 14 or more of, any 15 ormore of, any 16 or more of, any 17 or more of, any 18 or more of, any 19or more of, any 20 or more of, any 21 or more of, any 22 or more of, any23 or more of, any 24 or more of, any 25 or more of, or all 26 ofoutcomes (a)-(z) described immediately above.

Parameters (a)-(z) can be measured in accordance with any clinicallyacceptable methodology. For example, triglycerides, total cholesterol,HDL-C and fasting blood sugar can be sample from serum and analyzedusing standard photometry techniques. VLDL-TG, LDL-C and VLDL-C can becalculated or determined using serum lipoprotein fractionation bypreparative ultracentrifugation and subsequent quantitative analysis byrefractometry or by analytic ultracentrifugal methodology. Apo A1, Apo Band hsCRP can be determined from serum using standard nephelometrytechniques. Lipoprotein (a) can be determined from serum using standardturbidimetric immunoassay techniques. LDL particle number and particlesize can be determined using nuclear magnetic resonance (NMR)spectrometry. Remnants lipoproteins and LDL-phospholipase A2 can bedetermined from EDTA plasma or serum and serum, respectively, usingenzymatic immunoseparation techniques. Oxidized LDL, intercellularadhesion molecule-1 and interleukin-6 levels can be determined fromserum using standard enzyme immunoassay techniques. APOC3 levels can bedetermined by known quantitative methods including, for example,antibody-based assays such as ELISA. These techniques are described indetail in standard textbooks, for example Tietz Fundamentals of ClinicalChemistry, 6^(th) Ed. (Burtis, Ashwood and Borter Eds.), WB SaundersCompany.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention has previously been treatedwith a therapeutic regimen that included administration of Lovaza®(e.g., a combination of Lovaza and fenofibrate) and has experienced anincrease in, or no decrease in, LDL-C levels and/or non-HDL-C levels. Inone such embodiment, Lovaza® therapy is discontinued and replaced by amethod of the present invention.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a fasting baselineabsolute plasma level of free EPA (or mean thereof in the case of asubject group) not greater than about 0.70 nmol/ml, not greater thanabout 0.65 nmol/ml, not greater than about 0.60 nmol/ml, not greaterthan about 0.55 nmol/ml, not greater than about 0.50 nmol/ml, notgreater than about 0.45 nmol/ml, or not greater than about 0.40 nmol/ml.In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a baseline fastingplasma level (or mean thereof) of free EPA, expressed as a percentage oftotal free fatty acid, of not more than about 3%, not more than about2.5%, not more than about 2%, not more than about 1.5%, not more thanabout 1%, not more than about 0.75%, not more than about 0.5%, not morethan about 0.25%, not more than about 0.2% or not more than about 0.15%.In one such embodiment, free plasma EPA and/or total fatty acid levelsare determined prior to initiating therapy.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a fasting baselineabsolute plasma level of total fatty acid (or mean thereof) not greaterthan about 250 nmol/ml, not greater than about 200 nmol/ml, not greaterthan about 150 nmol/ml, not greater than about 100 nmol/ml, or notgreater than about 50 nmol/ml.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a fasting baselineplasma, serum or red blood cell membrane EPA level not greater thanabout 70 μg/ml, not greater than about 60 μg/ml, not greater than about50 μg/ml, not greater than about 40 μg/ml, not greater than about 30μg/ml, or not greater than about 25 μg/ml.

In another embodiment, methods of the present invention comprise a stepof measuring the subject's (or subject group's mean) baseline lipidprofile prior to initiating therapy. In another embodiment, methods ofthe invention comprise the step of identifying a subject or subjectgroup having one or more of the following: baseline non-HDL-C value ofabout 200 mg/dl to about 400 mg/dl, for example at least about 210mg/dl, at least about 220 mg/dl, at least about 230 mg/dl, at leastabout 240 mg/dl, at least about 250 mg/dl, at least about 260 mg/dl, atleast about 270 mg/dl, at least about 280 mg/dl, at least about 290mg/dl, or at least about 300 mg/dl; baseline total cholesterol value ofabout 250 mg/dl to about 400 mg/dl, for example at least about 260mg/dl, at least about 270 mg/dl, at least about 280 mg/dl or at leastabout 290 mg/dl; baseline VLDL-C value of about 140 mg/dl to about 200mg/dl, for example at least about 150 mg/dl, at least about 160 mg/dl,at least about 170 mg/dl, at least about 180 mg/dl or at least about 190mg/dl; baseline HDL-C value of about 10 to about 60 mg/dl, for examplenot more than about 40 mg/dl, not more than about 35 mg/dl, not morethan about 30 mg/dl, not more than about 25 mg/dl, not more than about20 mg/dl, or not more than about 15 mg/dl; and/or baseline LDL-C valueof about 50 to about 300 mg/dl, for example not less than about 100mg/dl, not less than about 90 mg/dl, not less than about 80 mg/dl, notless than about 70 mg/dl, not less than about 60 mg/dl or not less thanabout 50 mg/dl.

In one embodiment, compositions of the invention are packaged in blisterpacks. In another embodiment, the blister packs comprise PCTFE (forexample 50μ laminated with water based adhesive to clear PVC (forexample 190μ which are heat sealed to aluminum foil).

In one embodiment, subjects fast for up to 12 hours prior to bloodsample collection, for example about 10 hours.

In another embodiment, the present invention provides a method of bloodlipid therapy comprising administering to a subject in need thereof 1 toa plurality of dosage units comprising a composition or compositions asdisclosed herein. In another embodiment, the subject being treated has abaseline triglyceride level, prior to treatment with a composition ofthe present invention, greater than or equal to about 150 mg/dl, greaterthan or equal to about 175 mg/dl, greater than or equal to about 200mg/dl, greater than or equal to about 250 mg/dl, or greater than orequal to 500 mg/dl, for example about 200 mg/dl to about 2000 mg/dl,about 200 mg/dl to 499 mg/dl, about 300 to about 1800 mg/dl, about 500mg/dl to about 1500 mg/dl, or 500 mg/dl to about 2000 mg/dl.

In another embodiment, the present invention provides a method oftreating or preventing primary hypercholesterolemia and/or mixeddyslipidemia (Fredrickson Types IIa and IIb) in a patient in needthereof, comprising administering to the patient one or morecompositions as disclosed herein. In a related embodiment, the presentinvention provides a method of reducing triglyceride levels in a subjector subjects when treatment with a statin or niacin extended-releasemonotherapy is considered inadequate (Frederickson type IVhyperlipidemia).

In a related embodiment, the present invention provides a method ofreducing triglyceride levels in a subject or subjects when treatmentwith a monotherapy is considered inadequate. Monotherapy is consideredinadequate when, for example, the subject's non-HDL-C level is notlowered or is not lowered to the degree desired, the subject's LDL-Clevel increases more than about 5% compared to baseline or to placebocontrol, the subject's LDL-C level is not improved or is not improved tothe degree desired, the subject's HDL-C level is not improved or is notimproved to the degree desired, and/or the subject's triglyceride levelis not improved or is not improved to the degree desired. In someembodiments, the monotherapy includes administration of Lovaza, ahydroxyl compound, or a statin.

In another embodiment, the present invention provides a method oftreating or preventing nonfatal myocardial infarction, comprisingadministering (e.g., co-administering) to the subject a composition orcompositions comprising EPA and a hydroxyl compound (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating or preventing risk of recurrent nonfatal myocardial infarctionin a subject with a history of myocardial infarction, comprisingadministering (e.g., co-administering) to the subject a composition orcompositions comprising EPA and a hydroxyl compound (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method ofslowing progression of or promoting regression of atheroscleroticdisease in a subject in need thereof, comprising administering (e.g.,co-administering) to the subject a composition or compositionscomprising EPA and a hydroxyl compound (either as a single dosage unitor as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating obesity in a subject in need thereof, comprising administering(e.g., co-administering) to a subject in need thereof a composition orcompositions comprising EPA and a hydroxyl compound (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating or preventing very high serum triglyceride levels (e.g, TypesIV and V hyperlipidemia) in a subject in need thereof, comprisingadministering (e.g., co-administering) to the subject a composition orcompositions comprising EPA and a hydroxyl compound (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating subjects having very high serum triglyceride levels (e.g.,greater than 1000 mg/dl or greater than 2000 mg/dl) and that are at riskof developing pancreatitis, comprising administering (e.g.,co-administering) to the subject a composition or compositionscomprising EPA and a hydroxyl compound (either as a single dosage unitor as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating subjects having homozygous familial hypercholesterolemia (HoFH)comprising administering (e.g., co-administering) to the subject acomposition or compositions comprising EPA and a hydroxyl compound(either as a single dosage unit or as multiple dosage units) asdisclosed herein.

In another embodiment, the present invention provides a method ofpreventing recurrence of stroke, comprising administering (e.g.,co-administering) to a subject with a history of stroke a composition orcompositions comprising EPA and a hydroxyl compound (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method ofpreventing onset and/or recurrence of cardiovascular events in a subjectwho has escaped the unstable period after cardiovascular angioplasty,comprising administering (e.g., co-administering) to the subject acomposition or compositions comprising EPA and a hydroxyl compound(either as a single dosage unit or as multiple dosage units) asdisclosed herein.

In another embodiment, the present invention provides a method ofreducing Apo-B and non-HDL cholesterol levels in a subject group with abaseline LDL-cholesterol level of at least 100 mg/dl, a baselinenon-HDL-cholesterol level of at least 130 mg/dl and a baselinetriglyceride level of at least 200 mg/dl, and reducing the Apo-B and thenon-HDL-cholesterol level of the subject group by administering (e.g.,co-administering) a composition or compositions comprising EPA and ahydroxyl compound (either as a single dosage unit or as multiple dosageunits) as disclosed herein to members of the subject group.

In another embodiment, the invention provides a method of reducing Apo-Blevels in a subject group, comprising measuring LDL-cholesterol,non-HDL-cholesterol, and triglyceride levels in subjects, providing asubject group with a baseline LDL-cholesterol level of at least 100mg/dL, a baseline non-HDL-cholesterol level of at least 130 mg/dL, and abaseline triglyceride level of at least 200 mg/dL, and reducing theApo-B levels of the subject group by administering (e.g.,co-administering) to members of the subject group a composition orcompositions comprising EPA and a hydroxyl compound (either as a singledosage unit or as multiple dosage units) as disclosed herein in anamount effective to reduce the Apo-B levels of the subject group in astatistically significant amount as compared to a control treatment,wherein an increase or statistically significant increase ofLDL-cholesterol level is avoided.

In another embodiment, the invention provides a method of reducing Apo-Blevels in a subject group, comprising providing a subject group with abaseline LDL-cholesterol level of at least 100 mg/dL, a baselinenon-HDL-cholesterol level of at least 130 mg/dL, and a baselinetriglyceride level of at least 200 mg/dL, reducing the Apo-B levels ofthe subject group by administering (e.g., co-administering) to membersof the subject group a composition or compositions comprising EPA and ahydroxyl compound (either as a single dosage unit or as multiple dosageunits) as disclosed herein in an amount effective to reduce the Apo-Blevels of the subject group in a statistically significant amount ascompared to a control treatment, and determining the reduction in theApo-B levels of the subject group.

In one embodiment, a composition of the invention is administered to asubject in an amount sufficient to provide a daily dose ofeicosapentaenoic acid of about 1 mg to about 10,000 mg, 25 about 5000mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about100 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg,about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg,about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, about 100 mg, about 125 mg, about150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg,about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg,about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg,about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg,about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, 2525 mg, about2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg,about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg,about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg,about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg,about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about3950 mg, about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg,about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg, about4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg,about 4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg,about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, about5000 mg, about 5025 mg, about 5050 mg, about 5075 mg, about 5100 mg,about 5125 mg, about 5150 mg, about 5175 mg, about 5200 mg, about 5225mg, about 5250 mg, about 5275 mg, about 5300 mg, about 5325 mg, about5350 mg, about 5375 mg, about 5400 mg, about 5425 mg, about 5450 mg,about 5475 mg, about 5500 mg, about 5525 mg, about 5550 mg, about 5575mg, about 5600 mg, about 5625 mg, about 5650 mg, about 5675 mg, about5700 mg, about 5725 mg, about 5750 mg, about 5775 mg, about 5800 mg,about 5825 mg, about 5850 mg, about 5875 mg, about 5900 mg, about 5925mg, about 5950 mg, about 5975 mg, about 6000 mg, about 6025 mg, about6050 mg, about 6075 mg, about 6100 mg, about 6125 mg, about 6150 mg,about 6175 mg, about 6200 mg, about 6225 mg, about 6250 mg, about 6275mg, about 6300 mg, about 6325 mg, about 6350 mg, about 6375 mg, about6400 mg, about 6425 mg, about 6450 mg, about 6475 mg, about 6500 mg,about 6525 mg, about 6550 mg, about 6575 mg, about 6600 mg, about 6625mg, about 6650 mg, about 6675 mg, about 6700 mg, about 6725 mg, about6750 mg, about 6775 mg, about 6800 mg, about 6825 mg, about 6850 mg,about 6875 mg, about 6900 mg, about 6925 mg, about 6950 mg, about 6975mg, about 7000 mg, about 7025 mg, about 7050 mg, about 7075 mg, about7100 mg, about 7125 mg, about 7150 mg, about 7175 mg, about 7200 mg,about 7225 mg, about 7250 mg, about 7275 mg, about 7300 mg, about 7325mg, about 7350 mg, about 7375 mg, about 7400 mg, about 7425 mg, about7450 mg, about 7475 mg, about 7500 mg, about 7525 mg, about 7550 mg,about 7575 mg, about 7600 mg, about 7625 mg, about 7650 mg, about 7675mg, about 7700 mg, about 7725 mg, about 7750 mg, about 7775 mg, about7800 mg, about 7825 mg, about 7850 mg, about 7875 mg, about 7900 mg,about 7925 mg, about 7950 mg, about 7975 mg, about 8000 mg, about 8025mg, about 8050 mg, about 8075 mg, about 8100 mg, about 8125 mg, about8150 mg, about 8175 mg, about 8200 mg, about 8225 mg, about 8250 mg,about 8275 mg, about 8300 mg, about 8325 mg, about 8350 mg, about 8375mg, about 8400 mg, about 8425 mg, about 8450 mg, about 8475 mg, about8500 mg, about 8525 mg, about 8550 mg, about 8575 mg, about 8600 mg,about 8625 mg, about 8650 mg, about 8675 mg, about 8700 mg, about 8725mg, about 8750 mg, about 8775 mg, about 8800 mg, about 8825 mg, about8850 mg, about 8875 mg, about 8900 mg, about 8925 mg, about 8950 mg,about 8975 mg, about 9000 mg, about 9025 mg, about 9050 mg, about 9075mg, about 9100 mg, about 9125 mg, about 9150 mg, about 9175 mg, about9200 mg, about 9225 mg, about 9250 mg, about 9275 mg, about 9300 mg,about 9325 mg, about 9350 mg, about 9375 mg, about 9400 mg, about 9425mg, about 9450 mg, about 9475 mg, about 9500 mg, about 9525 mg, about9550 mg, about 9575 mg, about 9600 mg, about 9625 mg, about 9650 mg,about 9675 mg, about 9700 mg, about 9725 mg, about 9750 mg, about 9775mg, about 9800 mg, about 9825 mg, about 9850 mg, about 9875 mg, about9900 mg, about 9925 mg, about 9950 mg, about 9975 mg, or about 10,000mg.

In one embodiment, a composition of the invention is administered to asubject in an amount sufficient to provide a daily dose of a hydroxylcompound of about 5 mg to about 2000 mg, for example about 5 mg, about10 mg, about 15 mg, about 20 mg, about 25 mg, about 28 mg, about 28.5mg, about 28.6 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg,about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg,about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg,about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg,about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg,about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg,about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg,about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg,about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg,about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg,about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg,about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg,about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg,about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg,about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg,about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, or about2000 mg.

In one embodiment, the composition is provided in a divided dose inorder to provide the desired daily dose of the hydroxyl compound and ofthe EPA. For example, a daily dose of about 40 mg, about 80 mg or about120 mg of the hydroxyl compound and about 4 g of EPA may be provided inone or a plurality of doses, such as 1 dose per day, 2 divided doses perday, 3 divided doses per day, 4 divided doses per day, 5 divided dosesper day, 6 divided doses per day, 7 divided doses per day, 8 divideddoses per day, 9 divided doses per day, 10 divided doses per day, ormore. Accordingly, a method of the present invention comprisesadministering to a subject 4 capsules per day, each capsule comprisingabout 10 mg, about 20 mg, or about 30 mg of the hydroxyl compound andabout 800 mg to about 1200 mg of ethyl eicosapentaenoate.

In one embodiment, compositions of the invention are orally deliverable.The terms “orally deliverable” or “oral administration” herein includeany form of delivery of a therapeutic agent or a composition thereof toa subject wherein the agent or composition is placed in the mouth of thesubject, whether or not the agent or composition is swallowed. Thus“oral administration” includes buccal and sublingual as well asesophageal administration.

In some embodiments, compositions of the invention are in the form ofsolid dosage forms. Non-limiting examples of suitable solid dosage formsinclude tablets (e.g. suspension tablets, bite suspension tablets, rapiddispersion tablets, chewable tablets, melt tablets, effervescenttablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hardgelatin capsule filled with solid and/or liquids), powder (e.g. apackaged powder, a dispensable powder or an effervescent powder),lozenges, sachets, cachets, troches, pellets, granules, microgranules,encapsulated microgranules, powder aerosol formulations, or any othersolid dosage form reasonably adapted for oral administration.

The fatty acid component (e.g., EPA) and the hydroxyl compound can beco-formulated in the same dosage unit, or can be individually formulatedin separate dosage units. The terms “dose unit” and “dosage unit” hereinrefer to a portion of a pharmaceutical composition that contains anamount of a therapeutic agent suitable for a single administration toprovide a therapeutic effect. Such dosage units may be administered oneto a plurality (e.g., 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2)of times per day, for example 1 to about 10 times per day, 1 to 8 timesper day, 1 to 6 times per day, 1 to 4 times per day, 1 to 2 times perday, once per day, twice per day, 3 times per day, 4 times per day, 5times per day, 6 times per day, 7 times per day, 8 times per day, 9times per day, 10 times per day, or as many times as needed to elicit atherapeutic response.

In one embodiment, a composition of the invention comprises a hydroxylcompound dispersed or suspended in EPA, wherein the dispersion orsuspension is present in a capsule (for example gelatin or HPMCcapsule), sachet, or other dosage form or carrier as described herein.

In another embodiment, the dispersion or suspension is substantiallyuniform. In still another embodiment, where co-administration of two ormore dosage units is desired, the EPA is present in a first dosage unit,for example a suspension in a capsule, and the hydroxyl compound ispresent in second dosage unit, for example a tablet. Optionally, anydesired additional agent can be present in a third composition.

In another embodiment, composition(s) of the invention can be in theform of liquid dosage forms or dose units to be imbibed directly or theycan be mixed with food or beverage prior to ingestion. Non-limitingexamples of suitable liquid dosage forms include solutions, suspension,elixirs, syrups, liquid aerosol formulations, etc.

In one embodiment, compositions of the invention, upon storage in aclosed container maintained at room temperature, refrigerated (e.g.about 5 to about 5-10° C.) temperature, or frozen for a period of about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about90%, at least about 95%, at least about 97.5%, or at least about 99% ofthe active ingredient(s) originally present therein.

In another embodiment, the present disclosure provides a method oftreating or preventing a cardiovascular-related disease or disorder in asubject receiving therapy including a hydroxyl compound as describedherein. In some embodiments, the method comprises administering to thesubject a composition comprising at least about 80%, at least about 90%,at least about 95%, at least about 96%, or greater than about 96%, byweight of all fatty acids (and/or derivatives thereof) present, ethyleicosapentaenoate. In some embodiments, the subject is administered thecomposition for a period of time to effect a reduction in triglyceridelevels, for example a reduction of at least about 5% (compared tobaseline, to placebo control, to a second subject or subject group whohas received ethyl eicosapentaenoate but not the hydroxyl compound, orto a second subject or subject group who has received the hydroxylcompound but not ethyl eicosapentaenoate). In some embodiments, thecardiovascular-related disease or disorder is hyperlipidemia orhomozygous familial hypercholesterolemia (HoFH). In some embodiments,the subject has a baseline fasting triglyceride level of about 200 mg/dlto about 499 mg/dl and is optionally on statin therapy (e.g., stablestatin therapy). In some embodiments, the subject has a baseline fastingtriglyceride level of at least about 500 mg/dl. In some embodiments, thehydroxyl compound and the composition comprising ethyl eicosapentaenoateare present in a single dosage form. In other embodiments, the hydroxylcompound is in a dosage form separate from the ethyl eicosapentaenoate.

In another embodiment, any of the methods disclosed herein are used intreatment or prevention of a subject or subjects that consume atraditional Western diet. In one embodiment, the methods of theinvention include a step of identifying a subject as a Western dietconsumer or prudent diet consumer and then treating the subject if thesubject is deemed a Western diet consumer. The term “Western diet”herein refers generally to a typical diet consisting of, by percentageof total calories, about 45% to about 50% carbohydrate, about 35% toabout 40% fat, and about 10% to about 15% protein. A Western diet mayalternately or additionally be characterized by relatively high intakesof red and processed meats, sweets, refined grains, and desserts, forexample more than 50%, more than 60% or more or 70% of total caloriescome from these sources.

What is claimed is:
 1. A composition comprising a hydroxyl compound andethyl eicosapentaenoate.
 2. The composition of claim 1, wherein thecomposition comprises at least about 80%, by weight of all fatty acids(and/or derivatives thereof) present, ethyl eicosapentaenoate.
 3. Thecomposition of claim 1, wherein the hydroxyl compound is present in anamount less than, about equal to, or greater than an effective amount ofthe hydroxyl compound when administered as a monotherapy.
 4. Thecomposition of any preceding claim, wherein the hydroxyl compound ispresent in an amount of about 5 mg to about 2000 mg.
 5. The compositionof claim 1, wherein the ethyl eicosapentaenoate is present in an amountof about 400 mg to about 5000 mg.
 6. The composition of claim 1, whereinthe hydroxyl compound is dispersed or suspended in the ethyleicosapentaenoate.
 7. The composition of claim 1, wherein the hydroxylcompound is 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.
 8. Amethod of treating or preventing a cardiovascular-related disease ordisorder in a subject comprising administering to the subject acomposition comprising a hydroxyl compound and a composition comprisingat least about 80%, by weight of all fatty acids (and/or derivativesthereof) present, ethyl eicosapentaenoate.
 9. The method of claim 8,wherein the cardiovascular-related disease or disorder is hyperlipidemiaor homozygous familial hypercholesterolemia (HoFH).
 10. The method ofclaim 8, wherein the subject has a baseline fasting triglyceride levelof about 200 mg/dl to about 499 mg/dl.
 11. The method of claim 10,wherein the subject is on statin therapy.
 12. The method of claim 8,wherein the subject has a baseline fasting triglyceride level of atleast about 500 mg/dl.
 13. The method of claim 8, wherein the subject isadministered the composition for a period of time to effect a reductionin triglyceride levels of at least about 5%.
 14. The method of claim 13,wherein the reduction is in comparison to baseline, to placebo controlor to a second subject or subject group who has received ethyleicosapentaenoate but not the hydroxyl compound.
 15. The method of claim13, wherein the reduction is in comparison to a second subject orsubject group who has received the hydroxyl compound but not ethyleicosapentaenoate.
 16. The method of claim 8, wherein the compositioncomprising the hydroxyl compound and the composition comprising ethyleicosapentaenoate are present in a single dosage form.
 17. The method ofclaim 8, wherein the hydroxyl compound is in a dosage form separate fromthe ethyl eicosapentaenoate.
 18. A method of treating or preventing acardiovascular-related disease or disorder in a subject receivingtherapy including a hydroxyl compound, the method comprisingadministering to the subject a composition comprising at least about80%, by weight of all fatty acids (and/or derivatives thereof) present,ethyl eicosapentaenoate.
 19. The method of claim 18, wherein the subjectis administered the composition for a period of time to effect areduction in triglyceride levels of at least about 5%.
 20. The method ofclaim 19, wherein the reduction is in comparison to baseline, to placebocontrol, to a second subject or subject group who has received ethyleicosapentaenoate but not the hydroxyl compound, or to a second subjector subject group who has received the hydroxyl compound but not ethyleicosapentaenoate.